Chroman derivative and pharmaceutical use thereof

ABSTRACT

Chroman derivatives of the formula  I! ##STR1## wherein R 1  is a cyano, a nitro, a trihalomethyl, a trihalomethoxy or a halogen atom; R 2  is a lower alkoxyalkyl, an aryloxyalkyl or a dialkoxyalkyl; R 3  is a lower alkoxyalkyl or an aryloxyalkyl; R 4  is a hydroxy, a formyloxy or a lower alkanoyloxy; X is N--H, an N--optionally substituted lower alkyl, an oxygen atom, a sulfur atom or a single bond; and Y is an optionally substituted aromatic ring residue or an optionally substituted heterocyclic residue, pharmaceutically acceptable salts thereof and pharmaceutical use thereof. The compound of the present invention and pharmaceutically acceptable salts thereof have selective and excellent coronary vasodilating action and extremely weak hypotensive action. Accordingly, it is possible to selectively increase the coronary blood flow without causing a sudden hypotention causative of tachycardia which has a detrimental effect on the heart, and they are useful as a coronary vasodilator, in particular, an agent for the prophylaxis and treatment of cardiovascular disorders such as angina pectoris and heart failure.

TECHNICAL FIELD

The present invention relates to a chroman derivative and pharmaceuticaluse thereof. More particularly, the present invention relates to achroman derivative having a selective and superior vasodilating actionon the coronary artery and useful as an agent for the prophylaxis andtreatment of cardiovascular disorders such as angina pectoris and heartfailure.

BACKGROUND ART

A potassium channel is concerned with a resting membrane potential.Activation of-the potassium channel leads to a resting membranepotential having moved toward the negative side (hyperpolarization),approaching the equilibrium potential of the potassium ion. In addition,activation of the potassium channel leads to the inhibition of theactivation of a potential-dependent calcium channel to result insuppression of an inflax of calcium, as well as promotion of anextracellular flow of the intracellular calcium which is due to asodium-calcium exchange reaction. The hyperpolarization of the membraneand lowered concentration of the intracellular free calcium which occursthereafter result in relaxation of smooth muscle, and then dilation ofblood vessels, to ultimately achieve hypotensive action and coronaryvasodilating action. A potassium channel is widely distributed in othersmooth muscles (e.g. trachea, intestine and uterus) and is known to alsorelax these muscles. Accordingly, a compound having a potassium channelactivating action is useful as an agent for the treatment or prophylaxisof hypertension, angina pectoris, heart failure, incontinence of urine,asthma and the like.

There have been already reported some compounds which activate thepotassium channel. For example, Japanese Patent Unexamined PublicationNos. 300182/1990 (corresponding to U.S. Pat. No. 5,104,890) and279377/1991 (corresponding to U.S. Pat. No. 5,095,016) disclose chromanderivatives wherein the 4-position amidino of benzopyran is modified bylower alkyl or phenyl, such as 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(N-cyano-acetimidoyl)amino!-2H-benzo b!pyran-3-ol and6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(N-cyano-benzimidoyl)amino!-2H-benzo b!pyran-3-ol; Japanese PatentUnexamined Publication Nos. 178850/1993 (corresponding to U.S. Pat. No.5,300,511) and 194496/1993 disclose chroman derivatives wherein one ofthe 2-position methyls of benzopyran is modified by dimethoxy, such as2-dimethoxymethyl-2-methyl-4-(3'-N-oxopyridyl)-6-cyano-2H-1-benzopyran.Japanese Patent Unexamined Publication No. 294954/1993 (EPO 632 033 A1)(corresponding to EPO 632 033 A1) happens to disclose a chromanderivative having, as one of the 2-position substituents,2,2-bismethoxymethyl, such as3-hydroxy-2,2-bismethoxymethyl-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide.The invention of said publication is, as is clear from the descriptiontherein, mainly characterized by the 4-position substituent of thebenzopyran ring and is not the compound of the present invention.Naturally, the publication merely recites conventionally known, ordinarypharmacological actions of potassium channel activating compounds, suchas those useful for an anti-asthma agent, a hypotensive agent, ananti-angina pectoris agent and a therapeutic agent for incontinence ofurine, and does not include a description indicating that such specificcompound has a selective coronary vasodilating action or even asuggestive remark to this effect. Moreover, Japanese Patent UnexaminedPublication No. 300880/1992 discloses a chroman derivative having, as a4-position substituent of benzopyran, an amino group substituted byheterocyclic residue, such as2,2-dimethyl-4-(1-methyl-1,6-dihydro-6-oxo-3-pyridazinylamino)-6-cyano-3-chromanol.However, the publication does not disclose substitution of the2-position of benzopyran with 2,2-bismethoxymethyl. Japanese PatentUnexamined Publication No. 66681/1991 discloses, as one of theexemplified compounds, a chroman derivative such as2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromanolwherein one of the 2-position methyls of benzopyran is modified bymethoxy, and also exemplifies1-methyl-1,6-dihydro-6-oxo-3-pyridazinyl-oxy as a 4-positionsubstituent. However, there is no suggestion to modify the 2-positiongroup of benzopyran with 2,2-bismethoxymethyl. Japanese PatentUnexamined Publication Nos. 300880/1992 and 66681/1991 teach that suchcompounds decrease resistance to blood flow in coronary artery whileretaining the influence on the heart rate small, thereby to increasecoronary blood flow. These known compounds do not necessarily showsufficient remediable effects against coronary vascular diseases such asheart failure, and a superior drug has been demanded.

DISCLOSURE OF THE INVENTION

The present inventors have conducted intensive studies with the aim offinding a compound having high selectivity and safer and superiorcoronary vasodilating action, and found that substitution of one of the2-position groups of benzopyran with lower alkoxyalkyl, aryloxyalkyl ordialkoxyalkyl, and the other with lower alkoxyalkyl or aryloxyalkyl,specifically a substitution of the 2-position groups of benzopyran withtwo lower alkoxyalkyl groups, in particular, 2,2-bismethoxymethyl,surprisingly results in a chroman derivative and a pharmaceuticallyacceptable salt thereof, which are effective for the prophylaxis andtreatment of the aforementioned cardiovascular diseases such as anginapectoris and heart failure, and which do not cause severe hypotentioncausative of tachycardia; namely, a chroman derivative and apharmaceutically acceptable salt thereof having a surprising selectivityand an excellent coronary vasodilating action beyond expectation, whichare pharmaceutically highly safe and cause minimum side-effects, whichresulted in the completion of the present invention.

That is, the chroman derivative of the present invention and a coronaryvasodilating agent containing same as a main ingredient are as follows.

(1) Chroman derivatives of the formula I! ##STR2## wherein R¹ is acyano, a nitro, a trihalomethyl, a trihalomethoxy or a halogen atom;

R² is a lower alkoxyalkyl, an aryloxyalkyl or a dialkoxyalkyl;

R³ is a lower alkoxyalkyl or an aryloxyalkyl;

R⁴ is a hydroxy, a formyloxy or a lower alkanoyloxy;

X is N--H, an N-optionally substituted lower alkyl, an oxygen atom, asulfur atom or a single bond; and

Y is an optionally substituted aromatic ring residue or an optionallysubstituted heterocyclic residue,

and pharmaceutically acceptable salts thereof.

(2) Chroman derivatives of the above (1) wherein R¹ is a cyano, a nitroor a halogen atom, R² is a lower alkoxyalkyl, R³ is a lower alkoxyalkyl,R⁴ is a hydroxy and X is N--H or an oxygen atom, and pharmaceuticallyacceptable salts thereof.

(3) Chroman derivatives of the above (2) wherein X is N--H, andpharmaceutically acceptable salts thereof.

(4) Chroman derivatives of the above (3) wherein R¹ is a cyano, andpharmaceutically acceptable salts thereof.

(5) Chroman derivatives of any one of the above (2) to (4), wherein R²is a methoxymethyl and R³ is a methoxymethyl, and pharmaceuticallyacceptable salts thereof.

(6) Chroman derivatives of the above (1), wherein the aromatic ringresidue at Y is a phenyl or the heterocyclic residue at Y is indolyl,pyrazolyl, imidazolyl, triazolyl, quinazolinyl, dihydrooxoquinazolinyl,isoquinolyl, dihydrooxoisoquinolyl, pyrimidinyl, dihydrooxopyrimidinyl,pyridazinyl, dihydrooxopyridazinyl, dihydrothioxopyridazinyl, pyridyl,dihydrooxopyridyl, phthalazinyl, dihydrooxophthalazinyl,pyridazinooxazinyl, tetrahydrooxo-2H-pyridazino 4,5-b!-1,4-oxazinyl,pyrazino 2,3-d!pyridazinyl, hexahydrooxopyrazino 2,3-d!pyridazinyl orpyridine-N-oxide, and pharmaceutically acceptable salts thereof.

(7) Chroman derivatives of the above (6) wherein R¹ is a cyano, a nitroor a halogen atom, R² is a lower alkoxyalkyl, R³ is a lower alkoxyalkyl,R⁴ is a hydroxy and X is N--H or an oxygen atom, and pharmaceuticallyacceptable salts thereof.

(8) Chroman derivatives of the above (7) wherein X is N--H, andpharmaceutically acceptable salts thereof.

(9) Chroman derivatives of the above (8) wherein R¹ is a cyano, andpharmaceutically acceptable salts thereof.

(10) Chroman derivatives of any one of the above (7) to (9), wherein R²is a methoxymethyl and R³ is a methoxymethyl, and pharmaceuticallyacceptable salts thereof.

(11) Chroman derivatives of the above (10) wherein X is N--H and Y is1,6-dihydro-1-lower alkyl-6-oxo-3-pyridazinyl or1,6-dihydro-1-substituted alkyl-6-oxo-3-pyridazinyl, andpharmaceutically acceptable salts thereof.

(12) Chroman derivatives of the above (1) which is selected from thegroup consisting of

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)oxy!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-3,4-dihydro-4-oxoquinazolin-2-ylthio!-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(3-cyano-1H-indol-1-yl)-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-4-(6-chloro-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(+)-(3S,4R)-6-cyano-4-(3-formyl-1H-indol-1-yl)-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-4-(6-acetyloxy-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-3-(trans-β-nitro)vinyl-1H-indol-1-yl!-2H-1-benzopyran-3-ol,

(-)-(Z)-1-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-3-hydroxy-2H-1-benzopyran-4-yl!-1H-indole-3-carboxyaldehydoxime,

(-)-(E)-1-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-3-hydroxy-2H-1-benzopyran-4-yl!-1H-indole-3-carboxyaldehydoxime,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(4-methoxycarbonyl-1H-pyrazol-1-yl)-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(1-ethyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-isopropyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(5-cyano-1H-indol-1-yl)-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(+)-(3S,4R)-6-cyano-3,4-dihydro-4-(3,4-dihydro-4-oxopyrimidin-3-yl)-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-phenoxy-2H-1-benzopyran-3-ol,

(±)-trans-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(+)-(3S,4R)-6-cyano-4-(2-cyanophenyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(4-cyanophenyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(pyrimidin-2-yl)amino!-2H-1-benzopyran-3-ol,

(+)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,4-dihydro-4-oxopyridin-1-yl)-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-4-(4-amino-1,2-dihydro-2-oxopyrimidin-1-yl)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(4-nitrophenoxy)-2H-1-benzopyran-3-ol,

(+)-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(1H-1,2,4-triazol-3-ylthio)-2H-1-benzopyran-3-ol,

(+)-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(1-methyl-1H-imidazol-2-ylthio)-2H-1-benzopyran-3-ol,

(+)-(3S,4R)-4-(3-amino-4H-1,2,4-triazol-4-yl)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olhydrate,

(+)-(3R,4S)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

trans-6-fluoro-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-bromo-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

trans-4-(6-chloro-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-4-(3-amino-1,6-dihydro-6-oxo-pyridazin-1-yl)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(3,4,7,8-tetrahydro-4,7-dimethyl-8-oxo-2H-pyridazino4,5-b!-1,4-oxazin-5-yl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(3,4,5,6-tetrahydro-4,6-dimethyl-5-oxo-2H-pyridazino4,5-b!-1,4-oxazin-8-yl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,2,3,4,5,6-hexahydro-1,4,6-trimethyl-5-oxopyrazino2,3-d!-pyridazin-8-yl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(3,4-dihydro-3-methyl-4-oxophthalazin-1-yl)!amino-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-thioxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(+)-(3S,4R)-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran-3-ol,

trans-4-(6-chloro-3-pyridazinyl)amino!-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

trans-6-fluoro-3,4-dihydro-4-(3,4-dihydro-3-methyl-4-oxophthalazin-1-yl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(2-pyridylamino)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(3-pyridylamino)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(4-pyridylamino)-2H-1-benzopyran-3-ol,

trans-6-fluoro-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-1-n-propyl-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(1-cyclopropylmethyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methoxyethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-n-heptyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-4-(1-allyl-1,6-dihydro-6-oxo-3-pyridazinyl)-amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-(methoxycarbonylmethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis-(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-(4-nitrophenyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-nitrophenyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(3S,4R)-4-(1-(benzyloxycarbonylmethyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methylthioethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-dimethylamino)ethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(1-cyanomethyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-4-(1-benzyl-1,6-dihydro-6-oxo-3-pyridazinyl)-amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-4-(1-(2-(E)-butenyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(1-(2-fluoroethyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(1-(2,2,2-trifluoroethyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

trans-6-fluoro-3,4-dihydro-4-(1,6-dihydro-6-oxo-1-n-propyl-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

trans-4-(1-(2-(E)-butenyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

trans-4-(1-allyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(3S,4R)-6-cyano-4-(1-ethyl-1,6-dihydro-6-oxo-3-pyridyl)-amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methylsulfonylethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis-(methoxymethyl)-2H-1-benzopyran-3-ol,

(+)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methylsulfinylethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis-(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(1-(2-cyanoethyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methoxycarbonylethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis-(methoxymethyl)-2H-1-benzopyran-3-ol,

trans-4-(1-(2-cyanoethyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

trans-6-fluoro-3,4-dihydro-4-(1,6-dihydro-1-(2-methoxycarbonylethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(3S,4R)-6-cyano-4-(1-(2-cyanoethyl)-1,6-dihydro-6-oxo-3-pyridyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methoxycarbonylethyl)-6-oxo-3-pyridyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-1-(2-nitroethyl)-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(1-(4-diethylamino-2-butyn-1-yl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis-(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-4-(1-carboxymethyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(4-fluorophenyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(4-fluoro-3-methylphenyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(+)-2-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-3-hydroxy-2H-1-benzopyran-4-ylamino!-pyridine-N-oxide,

(+)-3-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-3-hydroxy-2H-1-benzopyran-4-ylamino!-pyridine-N-oxide,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,2-dihydro-1-oxo-isoquinolin-2-yl)-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(+)-(3S,4R)-6-cyano-3,4-dihydro-4-(2,3-dihydro-3-oxoi-soquinolin-2-yl)-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(3,4-dihydro-3-methyl-4-oxophthalazin-1-yl)oxy!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1,4,5-trimethyl-6-oxo-3-pyridazinyl)oxy!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-bromo-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)oxy!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-oland

(-)-(3S,4R)-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)oxy!-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran-3-ol,and pharmaceutically acceptable salts thereof.

(13) Chroman derivatives of the above (1) which is selected from thegroup consisting of

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-4-(1-ethyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-isopropyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,

(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olhydrate and

(-)-(3S,4R)-6-cyano-4-(1-cyclopropylmethyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,and pharmaceutically acceptable salts thereof.

(14) Pharmaceutical compositions comprising a chroman derivative of anyone of the above (1) to (12) or a pharmaceutically acceptable saltthereof.

(15) Pharmaceutical compositions comprising a chroman derivative of theabove (13) or a pharmaceutically acceptable salt thereof.

(16) Pharmaceutical compositions of the above (14) or (15), which is acoronary vasodilator.

Throughout the present specification, the symbols used for variousdefinitions mean the following.

The lower alkyl represented by X is a straight or branched alkyl having1 to 5, preferably 1 to 4 carbon atoms, which is exemplified by methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl and 1,1-dimethylpropyl.

The lower alkoxyalkyl represented by R² and R³ is an alkoxyalkyl whereinthe total carbon number of the alkoxy moiety and alkyl moiety is 2 to 6,preferably 2 to 5 and the alkoxy moiety and the alkyl moiety may bestraight or branched. Specific examples include methoxymethyl,1-methoxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2-methoxypropyl,1-methoxypropyl, 1-methoxy-1-methylethyl, ethoxymethyl, propoxymethyl,isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl,tert-butoxymethyl and pentoxymethyl, with preference given tomethoxymethyl, 1-methoxyethyl and 2-methoxyethyl and particularpreference given to methoxymethyl. When the occasion demands, R² and R³may combinedly form --CH₂ --O--CH₂ --O--CH₂ --.

The dialkoxyalkyl represented by R² is a dialkoxyalkyl having 3 to 8,preferably 3 to 5 carbon atoms which is a lower alkyl wherein two loweralkoxy groups are bonded, as mentioned above. Examples thereof includedimethoxymethyl, 1,1-dimethoxyethyl, 1,2-dimethoxyethyl,2,2-dimethoxyethyl, 1,1-dimethoxypropyl, 1,2-dimethoxypropyl,1,3-dimethoxypropyl, 2,2-dimethoxypropyl, 2,3-dimethoxypropyl,3,3-dimethoxypropyl, 1,1-dimethoxybutyl, 1,2-dimethoxybutyl,1,3-dimethoxybutyl, 1,4-dimethoxybutyl, 2,2-dimethoxybutyl,2,3-dimethoxybutyl, 2,4-dimethoxybutyl, 3,3-dimethoxybutyl,3,4-dimethoxybutyl, 4,4-dimethoxybutyl, methoxyethoxymethyl,1-methoxy-1-ethoxyethyl, 1-methoxy-2-ethoxyethyl,2-methoxy-1-ethoxyethyl, 2-methoxy-2-ethoxyethyl,1-methoxy-1-ethoxypropyl, 1-methoxyl-2-ethoxypropyl,1-methoxy-3-ethoxypropyl, 2-methoxy-1-ethoxypropyl,2-methoxy-2-ethoxypropyl, 2-methoxy-3-ethoxypropyl,3-methoxy-1-ethoxypropyl, 3-methoxy-2-ethoxypropyl,3-methoxy-3-ethoxypropyl, 1-methoxymethyl-2-ethoxyethyl,1-methoxy-1-ethoxybutyl, 1-methoxy-2-ethoxybutyl,1-methoxy-3-ethoxybutyl, 1-methoxy-4-ethoxybutyl,2-methoxy-1-ethoxybutyl, 2-methoxy-2-ethoxybutyl,2-methoxy-3-ethoxybutyl, 2-methoxy-4-ethoxybutyl,3-methoxy-1-ethoxybutyl, 3-methoxy-2-ethoxybutyl,3-methoxy-3-ethoxybutyl, 3-methoxy-4-ethoxybutyl,4-methoxy-1-ethoxybutyl, 4-methoxy-2-ethoxybutyl,4-methoxy-3-ethoxybutyl, 4-methoxy-4-ethoxybutyl, diethoxymethyl,1,1-diethoxyethyl, 1,2-diethoxyethyl, 2,2-diethoxyethyl,1,1-diethoxypropyl, 1,2-diethoxypropyl, 1,3-diethoxypropyl,2,2-diethoxypropyl, 2,3-diethoxypropyl, 3,3-diethoxypropyl,1,1-diethoxybutyl, 1,2-diethoxybutyl, 1,3-diethoxybutyl,1,4-diethoxybutyl, 2,2-diethoxybutyl, 2,3-diethoxybutyl,2,4-diethoxybutyl, 3,3-diethoxybutyl, 3,4-diethoxybutyl and4,4-diethoxybutyl, with preference given to dimethoxymethyl,1,1-dimethoxyethyl, 1,2-dimethoxyethyl and 2,2-diethoxyethyl andparticular preference given to dimethoxymethyl.

The lower alkanoyloxy represented by R⁴ is an alkanoyloxy having 2 to 6,preferably 2 to 4 carbon atoms, which is exemplified by acetyloxy,propionyloxy, butyryloxy, valeryloxy and hexanoyloxy, with preferencegiven to acetyloxy and propionyloxy and particular preference given toacetyloxy.

The halogen atom represented by R¹ is fluorine atom, chlorine atom,bromine atom or iodine atom, with preference given to fluorine atom,chlorine atom and bromine atom.

The trihalomethyl represented by R¹ is a methyl substituted by threeoptional halogen atoms as mentioned above, which is exemplified bytrifluoromethyl, trichloromethyl and tribromomethyl, with preferencegiven to trifluoromethyl.

The trihalomethoxy represented by R¹ is a methoxy substituted by threeoptional halogen atoms as mentioned above, which is exemplified bytrifluoromethoxy, trichloromethoxy and tribromomethoxy, with preferencegiven to trifluoromethoxy.

The aromatic ring residue represented by Y is, for example, phenyl,naphthyl or biphenyl, with preference given to phenyl and naphthyl andparticular preference given to phenyl.

The heterocyclic residue is a 5- or 6-membered heterocyclic residuehaving 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom andsulfur atom, besides carbon atom, as an atom constituting the ring, andmay be a condensed ring residue. Examples thereof include indolyl,pyrazolyl, imidazolyl, triazolyl (e.g. 1,2,3-triazolyl and1,2,4-triazolyl), quinazolinyl, dihydrooxoquinazolinyl (e.g.3,4-dihydro-4-oxoquinazolinyl and 1,2-dihydro-2-oxoquinazolinyl),isoquinolyl, dihydrooxoisoquinolyl (e.g. 1,2-dihydro-1-oxoisoquinolyland 2,3-dihydro-3-oxoisoquinolyl), pyrimidinyl, dihydrooxopyrimidinyl(e.g. 1,2-dihydro-2-oxopyrimidinyl and 3,4-dihydro-4-oxopyrimidinyl),pyridazinyl, dihydrooxopyridazinyl (e.g. 1,6-dihydro-6-oxopyridazinyl),dihydrothioxopyridazinyl (e.g. 1,6-dihydro-6-thioxopyridazinyl),pyridyl, dihydrooxopyridyl (e.g. 1,2-dihydro-2-oxopyridyl and1,4-dihydro-4-oxopyridyl), phthalazinyl, dihydrooxophthalazinyl (e.g.1,2-dihydro-1-oxophthalazinyl), pyridazinooxazinyl (e.g. 2H-pyridazino4,5-b!-1,4-oxazinyl), tetrahydrooxo-2H-pyridazino 4,5-b!-1,4-oxazinyl(e.g. 3,4,5,6-tetrahydro-5-oxo-2H-pyridazino 4,5-b!-1,4-oxazinyl and3,4,7,8-tetrahydro-8-oxo-2H-pyridazino 4,5-b!-1,4-oxazinyl), pyrazino2,3-d!pyridazinyl, hexahydrooxopyrazino 2,3-d!pyridazinyl (e.g.1,2,3,4,5,6-hexahydro-5-oxopyrazino 2,3-d!-pyridazinyl),pyridine-N-oxide, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl,oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, triazinyl,indolinyl, isoindolinyl, oxoindolinyl, dioxoisoindolinyl, oxoindazolyl,dithiazolyl, dioxolanyl, dithiolyl, pyrrolidinyl, dithiadiazinyl,thiadiazinyl, morpholinyl, oxazinyl, thiazinyl, piperazinyl,piperidinyl, piperazinone, tetrahydrodioxopyrimidinyl,tetrahydrooxopyridazinyl, dihydrooxopyrazinyl, dihydrooxopyrazolyl,tetrazolyl, tetrazinyl, pyranyl, thiopyranyl, furoisoxazolyl,imidazothiazolyl, thienoisothiazolyl, thienothiazolyl, imidazopyrazolyl,cyclopentapyrazolyl, pyrrolopyrrolyl, cyclopentathienyl, thienothienyl,oxadiazolopyrazinyl, benzofurazanyl, thiadiazolopyrimidinyl,triazolothiazinyl, triazolopyrimidinyl, triazolopyridinyl,benzotriazolyl, oxazolopyrimidinyl, oxazolopyridinyl, benzoxazolyl,thiazolopyridazinyl, thiazolopyrimidinyl, benzoisothiazolyl,benzothiazolyl, pyrazolotriazinyl, pyrazolothiazinyl, imidazopyrazinyl,purinyl, pyrazolopyridazinyl, pyrazolopyrimidinyl, imidazopyridinyl,pyranopyrazolyl, benzimidazolyl, benzoxathiolyl, benzodioxalyl,dithiolopyrimidinyl, benzodithiolyl, indolizinyl, isoindolyl,furopyrimidinyl, furopyridinyl, benzofuranyl, isobenzofuranyl,thienopyrazinyl, thienopyrimidinyl, thienodioxynyl, thienopyridinyl,benzothienyl, cyclopentaoxazinyl, cyclopentafuranyl, benzothiadiazinyl,benzotriazinyl, pyridoxazinyl, benzoxazinyl, pyrimidothiazinyl,benzothiazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl,pyridopyridazinyl, pyridopyrimidinyl, cinnolinyl, quinoxalinyl,benzoxathiinyl, benzodioxynyl, benzodithiinyl, naphthylidinyl, quinolyl,benzopyranyl and benzothiopyranyl. Preferred are indolyl, pyrazolyl,imidazolyl, triazolyl (e.g. 1,2,4-triazolyl), quinazolinyl,dihydrooxoquinazolinyl (e.g. 3,4-dihydro-4-oxoquinazolinyl),isoquinolyl, dihydrooxoisoquinolyl (e.g. 1,2-dihydro-1-oxoisoquinolyl,2,3-dihydro-3-oxoisoquinolyl), pyrimidinyl, dihydrooxopyrimidinyl (e.g.1,2-dihydro-2-oxopyrimidinyl, 3,4-dihydro-4-oxopyrimidinyl),pyridazinyl, dihydrooxopyridazinyl (e.g. 1,6-dihydro-6-oxopyridazinyl),dihydrothioxopyridazinyl (e.g. 1,6-dihydro-6-thioxopyridazinyl),pyridyl, dihydrooxopyridyl (e.g. 1,2-dihydro-2-oxopyridyl,1,4-dihydro-4-oxopyridyl), phthalazinyl, dihydrooxophthalazinyl (e.g.1,2-dihydro-1-oxophthalazinyl), pyridazinooxazinyl (e.g. 2H-pyridazino4,5-b!-1,4-oxazinyl), tetrahydrooxo-2H-pyridazino 4,5-b!-1,4-oxazinyl(e.g. 3,4,5,6-hexahydro-5-oxo-2H-pyridazino 4,5-b!-1,4-oxazinyl,3,4,7,8-tetrahydro-8-oxo-2H-pyridazino 4,5-b!-1,4-oxazinyl), pyrazino2,3-d!pyridazinyl, hexahydrooxopyrazino 2,3-d!-pyridazinyl (e.g.1,2,3,4,5,6-hexahydro-5-oxopyrazino 2,3-d!-pyridazinyl) andpyridine-N-oxide.

When X is a single bond, Y is preferably a heterocyclic ring having atleast one nitrogen atom. It is desirable that the nitrogen atom on thehetero ring be directly bonded to the 4-position of chroman. When X isN--H, an N-optionally substituted lower alkyl, oxygen atom or sulfuratom, Y is preferably of a type wherein the carbon atom on theheterocyclic ring is directly bonded to X. When a selective coronaryvasodilation is considered, X is particularly preferably N--H. Y--X-- ispreferably 1,6-dihydro-6-oxo-3-pyridazinyl-amino or1,6-dihydro-6-oxo-3-pyridazinyloxy, with particular preference given to1,6-dihydro-6-oxo-3-pyridazinylamino.

"Optionally substituted" in the definition of X and Y means that thegroup may be substituted by 1 to 3 substituents which may be the same ordifferent. Specific examples include alkyl such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,hexyl, heptyl and octyl the alkyl may be substituted by nitro, halogenatom (as defined above), cyano, lower alkoxy (as defined later),cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl),alkylsulfonyl (as defined later), alkylsulfinyl (e.g. methylsulfinyl,ethylsulfinyl, propylsulfinyl and butylsulfinyl), carboxyl, amino,alkylamino (as defined later), dialkylamino (as defined later),alkylthio (as defined later), aralkyloxycarbonyl (e.g.benzyloxycarbonyl, phenethyloxycarbonyl and phenylpropyloxycarbonyl) andalkoxycarbonyl (as defined later)!; lower alkoxy such as methoxy,ethoxy, propoxy, butoxy and tert-butoxy; halogen atom; nitro; cyano;hydroxy; alkenyl or alkynyl having 2 to 4 carbon atoms such as vinyl,propenyl, butenyl, ethynyl, propinyl and butynyl these may besubstituted by dialkylamino (as defined later)!; acyl such as formyl,acetyl, propionyl, butyryl, isobutyryl, benzoyl and naphthoyl; acyloxysuch as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxyand benzoyloxy; nitroalkenyl such as nitrovinyl, nitropropenyl andnitrobutenyl; aryl such as phenyl, naphthyl and biphenyl the aryl may besubstituted by nitro, cyano or acyl (as defined above)!; aralkyl such asbenzyl; aralkyloxy such as benzyloxy, phenetyloxy and phenylpropyloxy;mercapto; alkylthio such as methylthio, ethylthio, propylthio,butylthio, isobutylthio and tert-butylthio; amino; alkylamino such asmethylamino, ethylamino, propylamino, diisopropylamino and butylamino;dialkylamino such as dimethylamino, diethylamino, dipropylamino,isopropylamino and dibutylamino; alkoxycarbonyl such as methoxycarbonyl,ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butoxycarbonyland tert-butoxycarbonyl; hydroxyiminomethyl; alkoxyiminomethyl; amido;phospholyl; sulfonyl; sulfonyloxy; sulfamoyl; alkylphosphoneamide suchas methylphosphoneamide, ethylphosphoneamide, propylphosphoneamide andisopropylphosphoneamide; methylenedioxy; alkoxyphospholyl such asmethoxyphospholyl, ethoxyphospholyl, propyloxyphospholyl andisopropyloxyphospholyl; alkylsulfonyl such as methylsulfonyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl andtert-butylsulfonyl; and alkylsulfonylamino such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino,butylsulfonylamino and tert-butylsulfonylamino. Preferred are alkyl suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl,hexyl and heptyl the alkyl may be substituted by nitro, halogen atom(e.g. fluorine atom and chlorine atom), cyano, lower alkoxy (as definedlater), cycloalkyl (e.g. cyclopropyl and cyclohexyl), alkylsulfonyl(e.g. methylsulfonyl and ethylsulfonyl), alkylsulfinyl (e.g.methylsulfinyl and ethylsulfinyl), carboxyl, dialkylamino (e.g.dimethylamino and diethylamino), alkylthio (e.g. methylthio andethylthio), aralkyloxycarbonyl (e.g. benzyloxycarbonyl) andalkoxycarbonyl (e.g. methoxycarbonyl and ethoxycarbonyl)!; halogen atom;nitro; cyano; hydroxy; alkenyl or alkynyl having 2 to 4 carbon atomssuch as vinyl, propenyl, butenyl, ethynyl, propinyl and butynyl thesemay be substituted by dialkylamino (e.g. dimethylamino anddiethylamino)!; acyl such as formyl, acetyl, propionyl and benzoyl;acyloxy such as formyloxy and acetyloxy; nitroalkenyl such asnitrovinyl, nitropropenyl and nitrobutenyl; aryl such as phenyl the arylmay be substituted by nitro, cyano and acyl (e.g. formyl and acetyl)!;aralkyl such as benzyl; amino; alkoxycarbonyl such as methoxycarbonyland butoxycarbonyl; and hydroxyiminomethyl.

The aryloxyalkyl represented by R² and R³ is a lower alkyl havingaryloxy, such as those mentioned above, which is exemplified byphenyloxymethyl, phenyloxyethyl, phenyoxypropyl, phenyloxyisopropyl,phenyloxybutyl, phenyloxypentyl, 1-naphthyloxymethyl,1-naphthyloxyethyl, 1-naphthyloxypropyl, 1-naphthyloxyisopropyl,1-naphthyloxybutyl, 1-naphthyloxypentyl, 2-naphthyloxymethyl,2-naphthyloxyethyl, 2-naphthyloxypropyl, 2-naphthyloxyisopropyl,2-naphthyloxybutyl, 2-naphthyloxypentyl, o-biphenyloxymethyl,o-biphenyloxyethyl, o-biphenyloxypropyl, o-biphenyloxyisopropyl,o-biphenyloxybutyl, o-biphenyloxypentyl, m-biphenyloxymethyl,m-biphenyloxyethyl, m-biphenyloxypropyl, m-biphenyloxyisopropyl,m-biphenyloxybutyl, m-biphenyloxypentyl, p-biphenyloxymethyl,p-biphenyloxyethyl, p-biphenyloxypropyl, p-biphenyloxyisopropyl,p-biphenyloxybutyl and p-biphenyloxypentyl, with preference given tophenyloxymethyl and 2-phenyloxyethyl.

As mentioned above, R¹ means cyano, nitro, trihalomethyl, trihalomethoxyor halogen atom. It is preferably cyano, nitro or halogen atom andparticularly preferably cyano. R² is lower alkoxyalkyl, aryloxyalkyl ordialkoxyalkyl, with preference given to lower alkoxyalkyl and particularpreference given to methoxymethyl. R³ is lower alkoxyalkyl oraryloxyalkyl, with preference given to lower alkoxyalkyl and particularpreference given to methoxymethyl. R⁴ is hydroxy, formyloxy or loweralkanoyloxy, with preference given to hydroxy. X is N--H, N--optionallysubstituted lower alkyl, oxygen atom, sulfur atom or a single bond, withpreference given to N--H, oxygen atom, sulfur atom and single bond, morepreference given to N--H and oxygen atom, and particular preferencegiven to N--H. Y is an optionally substituted aromatic ring residue oran optionally substituted heterocyclic residue, which is preferablyphenyl, indolyl, pyrazolyl, imidazolyl, triazolyl, quinazolinyl,dihydrooxoquinazolinyl, isoquinolyl, dihydrooxoisoquinolyl, pyrimidinyl,dihydrooxopyrimidinyl, pyridazinyl, dihydrooxopyridazinyl,dihydrothioxopyridazinyl, pyridyl, dihydrooxopyridyl, phthalazinyl,dihydrooxophthalazinyl, pyridazinoxazinyl, tetrahydrooxo-2H-pyridazino4,5-b!-1,4-oxazinyl, pyrazino 2,3-d!pyridazinyl, hexahydrooxopyrazino2,3-d!pyridazinyl or pyridine-N-oxide, with preference given todihydrooxopyridazinyl and more preference given to 1,6-dihydro-1-loweralkyl-6-oxo-3-pyridazinyl and 1,6-dihydro-1-substitutedalkyl-6-oxo-3-pyridazinyl.

The pharmaceutically acceptable salts are exemplified by, but notlimited to, acid addition salts of various inorganic acids, such ashydrochloride, hydrobromide, sulfate, phosphate and nitrate; acidaddition salts of various organic acids, such as acetate, propionate,succinate, glycolate, lactate, malate, tartrate, citrate, maleate,fumarate, methanesulfonate, p-toluenesulfonate and ascorbate; and acidsof various amino acids, such as aspartate and glutamate.

The compound of the formula I! has two or more asymmetric carbons andthere exist optically pure diastereomers, racemates thereof and mixturesthereof at optional combinations and ratios, which are all encompassedin the present invention. In the case of racemates, only one opticallyactive compound can be obtained as necessary by optical resolution. Byasymmetric synthesis, only one optically active compound can be directlyobtained.

The present invention also encompasses hydrates of the compound of theformula I!.

The production methods for the chroman derivatives (hereinafter alsoreferred to as Compound I!) of the present invention are described inthe following. Needless to say that the production method is not limitedto those exemplified in the following. ##STR3## General productionmethod Step 1

2-Hydroxyacetophenon (compound 1, R¹ is as defined above) and compound 2wherein R² and R³ are as defined above are refluxed under heating in asolvent such as benzene, chlorobenzene, toluene and xylene, in thepresence of a secondary amine such as pyrrolidine, piperidine andmorpholine, using a Dean-Stark apparatus, while removing liberated waterto give 4-chromanon (compound 3 wherein R¹, R² and R³ are as definedabove).

In the present reaction, addition of a small amount of an acid catalystsuch as acetic acid, benzoic acid and p-toluenesulfonic acid often leadsto preferable results. Alternatively, the compound 3 can be produced bypreparing enamine from compound 2 and a secondary amine by aconventional method and reacting the enamine with compound 1. While thecompound 1 is mostly a commercially available one, in the contrary case,it can be prepared from p-substituted phenol by acetylation of theortho-position by Friedel-Crafts reaction or Fries rearrangement.

Step 2

The compound 3 is reduced using a reducing agent such as sodium boronhydride in a solvent such as methanol, ethanol and tetrahydrofuran,preferably in an alcohol solvent such as methanol and ethanol, undercooling to room temperature to give 4-chromanol (compound 4 wherein R¹,R² and R³ are as defined above).

Step 3

The compound 4 is refluxed under heating in a solvent such as benzene,chlorobenzene, toluene and xylene, in the presence of an acid catalystsuch as p-toluenesulfonic acid and camphor sulfonic acid, using aDean-Stark apparatus, while removing liberated water, or the hydroxylgroup of compound 4 is activated into acetyl, trifluoroacetyl,methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl usingacetic anhydride, trifluoroacetic acid, methanesulfonyl chloride,trifluoromethanesulfonyl chloride or p-toluenesulfonyl chloride andremoving the activated hydroxy using a base such as triethylamine,N-methylmorpholine and diazabicycloundecene, particularly preferablydiazabicycloundecene, to give a chromene (compound 5 wherein R¹, R² andR³ are as defined above).

Step 4

The compound 5 is oxidized with an oxidizing agent such asm-chloroperbenzoic acid and peracetic acid in a solvent such aschloroform, methylene chloride and ether, under cooling to roomtemperature to give 3,4-epoxychroman (compound 6 wherein R¹, R² and R³are as defined above).

Alternatively, the conversion from compound 5 to compound 6 can beperformed in plural steps. That is, compound 5 is converted tobromohydrin compound with N-bromosuccinimide and the like in the mixedsolvents of solvents such as methylene chloride, chloroform, ether,dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, methanol and ethanol, and water, and hydrogen bromide isremoved from the obtained compound, using a base such as sodiumhydroxide to give the compound 6.

Furthermore, the optically active compound 6 can be produced bystereoselectively oxidizing the compound 5 using a Mn(III)-Salen complexas described in J. Am. Chem. Soc., 113, 7063 (1991) and Journal ofSynthetic Organic Chemistry, Japan, vol. 51, No. 5, p. 412 (1993).

Step 5

A compound Y--X--H wherein Y and X are as defined above or a derivativethereof, as exemplified by oxodihydropyridazinyl derivative described inJ. Med. Chem, 34, 3074 (1991), such as primary or secondary aminecompound, alcohol derivative, thioalcohol derivative having variousheterocycles, and primary or secondary amine compound, alcoholderivative and thioalcohol derivative having aromatic rings, is reactedwith a solution of compound 6 in a polar aprotic solvent (e.g.dimethylformamide and dimethyl sulfoxide), alcohol solvent (e.g.methanol and ethanol) or a mixed solvent thereof, in the presence orabsence of a base such as alkali metal hydride (e.g. sodium hydride andpotassium hydride), alkaline earth metal hydride (e.g. calcium hydride),alkali metal carbonate (e.g. potassium carbonate and sodium carbonate),metal alcoholate (e.g. potassium tert-butoxide), pyridine,N-methylmorpholine, triethylamine and alkali metal hydroxide (e.g.potassium hydroxide and sodium hydroxide) from room temperature toheating to give a compound I-a (a Compound I! wherein R⁴ is hydroxy andR¹, R², R³, X and Y are as defined above).

When a compound wherein Y is 1,6-dihydro-6-oxopyridazinyl is desired, acompound I-a wherein Y is 6-chloropyridazinyl, which is obtainedaccording to the general production method as mentioned above, isreacted in acetic acid as a solvent added with an alcohol solvent suchas methanol and ethanol on demand, in the presence of potassium acetateor sodium acetate and, where necessary, in the presence of a base suchas potassium hydroxide and sodium hydroxide from room temperature toheating.

When Y is a substituted heterocyclic residue, such as1,6-dihydro-6-oxopyridazinyl or 1,6-dihydro-6-oxopyridyl substituted bymethyl, ethyl, propyl, isopropyl, heptyl, cyclopropylmethyl, allyl,cyanomethyl, cyanoethyl, nitroethyl, methoxycarbonylmethyl,methoxycarbonylethyl, 2-nitrophenyl, 4-nitrophenyl, 2-fluoroethyl,2,2,2-trifluoroethyl, benzyl, (dimethylamino)ethyl,benzyloxycarbonylmethyl, 2-methylthioethyl, methoxyethyl, 2-butenyl,diethylamino-2-butyn-1-yl, carboxymethyl, methylsulfonylethyl ormethylsulfinylethyl, the following method is applied. That is, acompound wherein Y is 1,6-dihydro-6-oxopyridazinyl or1,6-dihydro-6-oxopyridyl is produced according to the general productionmethod as described above. The compound is reacted with a startingcompound corresponding to respective substituents, such as methyliodide, ethyl iodide, isopropyl bromide, propane bromide,cyclopropylmethyl bromide, heptyl bromide, allyl bromide,bromoacetonitrile, nitroethanol, methyl bromoacetate, methyl acrylate,acrylonitrile, 2-fluoronitrobenzene, 4-fluoronitrobenzene,1-bromo-2-fluoroethane, 2,2,2-trifluoroethyl iodide, benzyl bromide,2-dimethylaminoethyl chloride, benzyl bromoacetate, methylthioethylchloride, methoxyethyl bromide, crotyl bromide and 1,4-dichloro-2-butynin a polar aprotonic solvent (e.g. dimethylformamide and dimethylsulfoxide), an alcohol solvent (e.g. methanol and ethanol) or a mixedsolvent thereof, in the presence or absence of a base such as alkalimetal hydride (e.g. sodium hydride and potassium hydride), alkalineearth metal hydride (e.g. calcium hydride), alkali metal carbonate (e.g.potassium carbonate and sodium carbonate), metal alcoholate (e.g.potassium tert-butoxide), pyridine, N-methylmorpholine, triethylamineand alkali metal hydroxide (e.g. potassium hydroxide and sodiumhydroxide) from room temperature to heating to give the desiredcompound.

When a compound wherein the substituent at the heterocyclic residue isnitroethyl is desired, an alcohol compound such as nitroethanol isreacted with methanesulfonyl chloride or toluenesulfonyl chloride in asolvent such as chloroform and dichloromethane, in the presence of abase such as pyridine and triethylamine to subject the alcohol compoundto methanesulfonylation or toluenesulfonylation. The obtained compoundis reacted in the presence of a base in the same manner as in theintroduction of a substituent to the above-mentioned heterocyclicresidue.

In particular, when a compound wherein the substituent at theheterocyclic residue is methylsulfonylethyl or methylsulfinylethyl isdesired, for example, 2-methylthioethyl as obtained in the above isoxidized with an oxidizing agent such as m-chloroperbenzoic acid.

When a compound wherein the substituent at the heterocyclic residue isdiethylamino-2-butyn-1-yl is desired, for example, a compound wherein Yis 1,6-dihydro-6-oxopyridazinyl is reacted with 1,4-dichloro-2-butyneand then with diethylamine.

When a compound wherein the substituent at the heterocyclic residue iscarboxymethyl is desired, for example, the benzyloxycarbonyl obtained inthe above reaction is subjected to catalytic reduction by hydrogenationin methanol as a solvent, in the presence of palladium-carbon.

A heteroaryl-N-oxide compound wherein Y is pyridine-N-oxide is obtainedby, according to the above-mentioned general production method,producing a compound wherein Y is pyridyl, and oxidizing the compoundobtained with an oxidizing agent such as m-chloroperbenzoic acid andperacetic acid, in a solvent such as chloroform, methylene chloride andether from cooling to heating, particularly preferably from ice-coolingto room temperature.

A heteroarylcarboxyaldehydoxime compound wherein Y is3-(hydroxyiminomethyl)indolyl is obtained by, according to theabove-mentioned general production method, producing aheteroarylcarboxyaldehyde compound wherein Y is 3-formylindolyl, andreacting the said compound in an alcohol solvent such as methanol andethanol as necessary, in the presence of a base such as pyridine andtriethylamine, and hydroxylamine hydrochloride at room temperature toheating.

Step 6

A compound I-b wherein R⁴ is lower alkanoyloxy or formyloxy and othersymbols are as defined above can be produced by converting the3-position hydroxy of compound I-a to alkanoyl or formyl by aconventional method. Namely, the compound I-a is subjected toalkanoylation by reacting the compound I-a with an acid chloride such asacetic chloride or an acid anhydride such as acetic anhydride, in asolvent such as chloroform and methylene chloride or without solvent, inthe presence of a base such as pyridine, lutidine and triethylamine fromice-cooling to room temperature. The compound I-a is subjected toformylation by treating the compound with formic acid or aceticanhydride, under reflux in a solvent which does not inhibit thereaction, such as methylene chloride and chloroform.

The Compound I! obtained can be isolated and purified by a methodconventionally known, such as recrystallization, column chromatographyand the like.

The pharmaceutically acceptable salts of Compound I! can be obtained bytreating the Compound I! with the aforementioned inorganic acid, organicacid or amino acid by a conventional method.

The Compound I! and pharmaceutically acceptable salts thereof of thepresent invention have surprising selectivity and excellent coronaryvasodilating action beyond expectation and are effective for theprophylaxis and treatment of cardiovascular disorders such as anginapectoris and heart failure. The Compound I! and pharmaceuticallyacceptable salts thereof of the present invention exert extremely weakinfluence on the hypotensive action. Accordingly, coronary blood flowcan be increased with surprising selectivity, without causing suddenhypotention causative of tachycardia which has a detrimental effect onthe heart. Consequently, they are useful as an agent for the prophylaxisand treatment of cardiovascular disorders such as angina pectoris andheart failure.

In addition, they are expected to show a relaxing action on the smoothmuscles other than cardiovascular smooth muscle. Therefore, they areexpected to be useful as a therapeutic agent for gastrointestinal tumor,irritable intestinal syndrome and diverticulum disorder, reversibletracheal obliterans and asthma, immature birth, incontinence of urineand cerebrovascular disorders.

It is expected that they are useful for the prevention and treatment ofalopecia such as areatic alopecia, when topically applied to the baldscalp.

When the Compound I! or a pharmaceutically acceptable salt thereof ofthe present invention is used as a pharmaceutical preparation, it isadmixed with a pharmacologically acceptable carrier, excipient, diluent,extender, disintegrator, stabilizer, preservative, buffer, emulsifier,aromatic, coloring agent, sweetener, thickener, flavor, solubilizer andother additives such as water, vegetable oil, alcohol such as ethanol,benzyl alcohol and hydroxypropyl alcohol, carbohydrate such aspolyethylene glycol, glycerol triacetate, gelatin, lactose and starch,magnesium stearate, talc, lanolin, petrolatum, lactose, sucrose,glucose, mannit, sorbit, crystalline cellulose, gum arabic, dextrin,pullulan, aluminum silicate, calcium phosphate, waxes, boric acid, DLleucin, fatty acid sodium, magnesium laurylsulfate, dextrin,hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol, carnaubawax, polyoxyethylene, polyoxypropylene, glycol, cacao butter, lauricacid, lecitin, glycerin, sodium p-oxybenzoate, sodium benzoate,salicylic acid and potassium sorbate to give a pharmaceuticalcomposition, which is formed into tablet, pill, powder, granule,suppository, injection, eye drop, liquid, capsule, troche, aerosol,elixir, suspension, emulsion, syrup and the like for oral or parenteraladministration.

While the dose varies depending on the kind and severity of diseases,compound to be administered and the administration route, age, sex andbody weight of patient and so on, the Compound I! or a pharmaceuticallyacceptable salt thereof of the present invention is preferablyadministered in 0.001-1,000 mg, particularly 0.1-100 mg orally to anadult per day.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the relationship among the compound of Example1, lemakalim(-)-(3S,4R)-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-2H-1-benzopyran-3-ol,reference compound a! and2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromanol(reference compound b) in changes (%) in mean blood pressure (abscissa)and changes (%) in coronary blood flow (ordinate).

FIG. 2 is a graph showing the relationship among the compound of Example28, lemakalim((-)-(3S,4R)-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-2H-1-benzopyran-3-ol,nicorandil and nifedipine in changes (%) in mean blood pressure(abscissa) and changes (%) in coronary blood flow (ordinate).

The results of the pharmacological evaluation of the compounds of thepresent invention are shown in the following.

Effect on coronary blood flow

EXPERIMENTAL EXAMPLE 1

Male and female mongrel adult dogs (9.5-15 kg) were anesthetized byintravenous administration of sodium pentobarbital (25 mg/kg). The dogswere fixed on their back and artificially ventilated (20 ml/kg, 18times/min) with an artificial respirator (SN-408-4, manufactured byShinano Seisakusho) after tracheal intubation. For continuousanesthesia, a catheter was inserted from the right femoral vein andsodium pentobarbital (3-5 mg/kg/hour) was continuously infused. Theblood pressure was measured via a KIFA catheter (17-867-1, manufacturedby Siemens Elema, Sweden) inserted from the left femoral artery toabdominal aorta, which was connected to a pressure transducer (TP-400T,manufactured by Nippon Koden). The coronary blood flow changes inducedby arterial administration and intravenous administration of compoundwere tested. The coronary blood flow was measured respectively by anelectromagnetic flow probe (FF-030T, manufactured by Nippon Koden)placed in an extracorporeal circulation system from the femoral arteryto the coronary artery, when a drug was intraarterially administered,and when a drug was intravenously administered, the coronary blood flowwas measured by an electromagnetic flowmeter via electromagnetic flowprobes (FJ-020T and FJ-025T, manufactured by Nippon Koden) which wereset at the left coronary circumflex after thoracotomy at left fifthcosta. These parameters were recorded on a recticorder (RJG-4128,manufactured by Nippon Koden).

The test solution was prepared by dissolving a sample in a mixedsolution of N,N-dimethylformamide (30%) and physiological saline (70%)and diluting with physiological saline as appropriate. The test solutionwas administered into the extracorporeal circulation system or the rightfemoral vein. The test compounds were the compound of Example 1 to bementioned later, lemakalim((-)-(3S,4R)-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-2H-1-benzopyran-3-ol(reference compound a) and2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromanol(low polarity isomer, reference compound b) disclosed in Japanese PatentUnexamined Publication No. 66681/1991).

When the compound of Example 1 of the present invention was administeredinto the coronary artery, the coronary blood flow increased. Based onthe blood flow increase by the coronary arterial administration ofnifedipine (1 μg) as 100%, the amount of the compound necessary toachieve 50% increase thereof, namely, ED₅₀, was 0.58 μg for the compoundof Example 1. At this dose, nifedipine caused marked hypotension,whereas it was not observed in the compound of the present invention.When the compound of Example 1 of the present invention wasintravenously administered in a dose of 1-10 μg/kg, the coronary bloodflow increased by 15-430%. According to a different test, the compoundof Example 1 was superior in duration, in comparison with the referencecompound b.

The relationship between the increase in coronary arterial blood flowand decrease in blood pressure induced by intravenous administration ofthe compounds is shown in FIG. 1. The dose of the intravenousadministration was 1, 2, 3, 5 or 10 μg/kg for the compound of Example 1of the present invention; 0.3, 1, 3 or 10 μg/kg for lemakalim (referencecompound a) and 10, 30 or 100 μg/kg for the reference compound b.

As shown in the Figure, the compound of Example 1 of the presentinvention caused only about 4% hypotension when 100% coronary blood flowincrease was intended, whereas the reference compound a caused about 9%hypotention, and the reference compound b caused about 13% hypotension.When 50% coronary blood flow increase was intended, the compound ofExample 1 of the present invention caused only about 2.5% hypotension,whereas the reference compound a caused about 5% (more than twice thepresent invention) and the reference compound b caused about 10% (morethan thrice the present invention) hypotension.

EXPERIMENTAL EXAMPLE 2

Male and female beagles (7-14 kg) were anesthetized by intravenousadministration of sodium pentobarbital (25 mg/kg). The dogs were fixedon their back and artificially ventilated (20 ml/kg, 18 times/min) withan artificial respirator (SN-408-4, manufactured by Shinano Seisakusho)after tracheal intubation. For continuous anesthesia, a catheter wasinserted from the right femoral vein and sodium pentobarbital (5mg/kg/hour) was persistently injected. The blood pressure was measuredvia a KIFA catheter (17-867-1, Semens Elema, Sweden) inserted from thefemoral artery to the abdominal aorta, which was connected to a pressuretransducer (TP-400T, manufactured by Nippon Koden). The coronary bloodflow was measured by an electromagnetic flowmeter via electromagneticflow probes (FJ-020T and FJ-025T, manufactured by Nippon Koden) whichwere set at the left coronary circumflexus after thoracotomy at thefifth left costa. These parameters were recorded on a stylus recticorder(RJG-4128, manufactured by Nippon Koden).

The test solution was prepared by dissolving a sample in a mixedsolution of N,N-dimethylformamide (30%) and physiological saline (70%)and diluting same with physiological saline as appropriate. The testsolution was administered into the right femoral vein. The testcompounds were the compound of Example 28 to be mentioned later,lemakalim((-)-(3S,4R)-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-2H-1-benzopyran-3-ol),nicorandil and nifedipine (all reference compounds).

When the compound of Example 28 of the present invention wasintravenously administered at 0.3-10 μg/kg, the coronary blood flowincreased by 6-270%.

The relationship between the increase in the coronary arterial bloodflow and decrease in blood pressure induced by intravenousadministration of the compounds is shown in FIG. 2. The doses of theintravenously administered reference compounds were 0.3, 1, 5 or 10μg/kg for lemakalim, 10, 30, 100 or 300 μg/kg for nicorandil and 0.1,0.3, 1, 3 or 10 μg/kg for nifedipine.

As shown in the Figure, the compound of Example 28 of the presentinvention caused only about 6% hypotension when 100% coronary blood flowincrease was intended, whereas lemakalim caused about 8.5% hypotension,nicorandil caused 7.5% hypotension and nifedipine caused 23%hypotension. When 50% coronary flow increase was intended, the compoundof Example 28 of the present invention caused only about 2.5%hypotension, whereas lemakalim and nicorandil caused about 5% (more thantwice the present invention) and nifedipine caused about 12% (more thanfour times the present invention) hypotension.

The present invention is described in more detail by PreparativeExamples and Examples, to which the present invention is not limited.

PREPARATIVE EXAMPLE 1

Production of compound 3 (R¹ =cyano, R²,R³ =methoxymethyl)

5-Cyano-2-hydroxyacetophenone (13.57 g) was dissolved in toluene (120ml), and pyrrolidine (6 ml) and 1,3-dimethoxy-2-propanone (15 ml) wereadded. The mixture was refluxed under heating for 1 hour while removingthe generated water. After cooling, the reaction mixture was dilutedwith ethyl acetate, washed with dilute hydrochloric acid, an aqueoussolution of sodium hydrogencarbonate and brine in order, and dried overanhydrous magnesium sulfate. The solvent was distilled away and theresidue obtained was purified by silica gel column chromatography (ethylacetate:hexane=2:8) to give 13.0 g of6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-one.

¹ H-NMR(CDCl₃ /ppm) δ2.95(2H, s), 3.35(6H, s), 3.55(2H, d, J=10.3 Hz),3.60(2H, d, J=10.3Hz), 7.07(1H, d), 7.68(1H), 8.14(1H).

PREPARATIVE EXAMPLE 2

Production of compound 4 (R¹ =cyano, R²,R³ =methoxymethyl)

6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-one (12.1g) obtained in Preparative Example 1 was dissolved in methanol (150 ml),and sodium boron hydride (1.96 g) was portionwise added with stirringunder ice-cooling. The mixture was stirred for 1.5 hours andconcentrated. Ice and ethyl acetate were added to the residue. Themixture was washed with water, dilute hydrochloric acid, an aqueoussolution of sodium hydrogencarbonate and brine in order, and dried overanhydrous magnesium sulfate. The solvent was distilled away to give 11.5g of 6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-ol.

¹ H-NMR(CDCl₃ /ppm) δ2.12(1H, dd, J=5.3 Hz, J=14.5 Hz), 2.33(1H, d,J=5.6 Hz, 14.5 Hz), 3.36(3H, s), 3.41(3H, s), 3.4-3.7(4H), 4.77(1H, m),6.92(1H, d), 7.44(1H, dd), 7.72(1H, d).

PREPARATIVE EXAMPLE 3

Production of compound 5 (R¹ =cyano, R²,R³ =methoxymethyl)

6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-ol (6.5 g)obtained in Preparative Example 2 was dissolved in toluene (60 ml), andp-toluenesulfonic acid (0.6 g) was added. The mixture was refluxed underheating for 1 hour while removing the generated water. The reactionmixture was concentrated, added with ethyl acetate, washed with water,an aqueous solution of sodium hydrogencarbonate and brine in order, anddried over anhydrous magnesium sulfate. The solvent was distilled awayand the residue obtained was purified by silica gel columnchromatography (ethyl acetate:hexane=3:17) to give 4.91 g of6-cyano-2,2-bis(methoxymethyl)-2H-1-benzopyran.

¹ H-NMR(CDCl₃ /ppm) δ3.39(6H, s), 3.55(2H, d, J=10.2 Hz), 3.60(2H, d,J=10.2 Hz), 5.76(1H, d, J=10.1 Hz), 6.49(1H, d, J=10.1 Hz), 6.87(1H, d),7.25(1H, d), 7.39(1H, dd).

PREPARATIVE EXAMPLE 4

Production of compound 6 (R¹ =cyano, R²,R³ =methoxymethyl)

6-Cyano-2,2-bis(methoxymethyl)-2H-1-benzopyran (4.3 g) obtained inPreparative Example 3 was dissolved in methylene chloride (50 ml), andm-chloroperbenzoic acid (4.75 g) was added under ice-cooling. Themixture was stirred at room temperature. m-Chloroperbenzoic acid wasadded (2.2 g 1 hour later and 1.5 g 18 hours later) and chloroform wasadded 21 hours later. The mixture was washed with a 1N aqueous solutionof sodium hydroxide, an aqueous solution of sodium hydrogencarbonate andbrine. After drying over anhydrous magnesium sulfate, the solvent wasdistilled away and the residue obtained was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:4) to give 4.05 g of6-cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran.

¹ H-NMR(CDCl₃ /ppm) δ3.27(3H, s), 3.48(3H, s), 3.57(1H, d, J=10.3 Hz),3.70(1H, d, J=10.3 Hz), 3.71(1H, s), 3.82(1H, d, J=4.4 Hz), 3.94(1H, d,J=4.4 Hz), 6.91(1H, d), 7.53(1H, dd), 7.65(1H, d).

PREPARATIVE EXAMPLE 5

Production of optically active compound of compound 6 (R¹ =cyano, R²,R³=methoxymethyl)

6-Cyano-2,2-bis(methoxymethyl)-2H-1-benzopyran (468 mg) obtained inPreparative Example 3 was added to a 0.5M aqueous solution of sodiumhypochlorite (8 ml) adjusted to pH 11.5 with a 0.05M phosphate bufferand a 1M aqueous solution of sodium hydroxide, and an Mn(III)-Salen(R,R) complex (25.5 mg) as described in J. Am. Chem. Soc., 113, 7063(1991) in methylene chloride (2 ml) was added under ice-cooling. Themixture was stirred for 17 hours under ice-cooling, extracted withmethylene chloride (3 times), dried, concentrated and subjected tosilica gel column chromatography (ethyl acetate:hexane=1:4) to give 398mg of an optically active compound of the compound of PreparativeExample 4,(3R,4R)-6-cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran(89% ee).

In the same manner, 451 mg of6-cyano-2,2-bis(methoxymethyl)-2H-1-benzopyran was oxidized using anMn(III)-Salen (S,S) complex as a catalyst to give 370 mg of(3S,4S)-6-cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran(94% ee).

PREPARATIVE EXAMPLE 6

Synthesis of methyl pyrazole-4-carboxylate

4-Pyrazolecarboxylic acid (514 mg) was dissolved in methanol (10 ml) andsulfuric acid (0.25 ml), and the mixture was stirred at room temperaturefor 2 hours, followed by refluxing under heating for 4 hours. Aftercooling, a 28% solution (0.95 ml) of sodium methylate in methanol wasadded to the reaction mixture for neutralization and the solvent wasdistilled away. Chloroform was added to the residue, and the residue waswashed with water and brine and dried over anhydrous magnesium sulfate.The solvent was distilled away to give 433 mg of the title compound.

¹ H-NMR(CDCl₃ /ppm) δ3.92(3H, s), 8.08(2H, s), 8.26(1H, br s)

PREPARATIVE EXAMPLE 7

Production of compound 3 (R¹ =nitro, R²,R³ =methoxymethyl)

By treating 2-hydroxy-5-nitroacetophenone in the same manner as inPreparative Example 1,3,4-dihydro-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran-4-one wasobtained.

¹ H-NMR(CDCl_(3/) ppm) δ2.97(2H, s), 3.35(6H, s), 3.56(2H, d), 3.62(2H,d), 7.10(1H, d), 8.31(1H, dd), 8.72(1H, d).

PREPARATIVE EXAMPLE 8

Production of compound 4 (R¹ =nitro, R²,R³ =methoxymethyl)

3,4-Dihydro-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran-4-oneobtained in Preparative Example 7 was treated in the same manner as inPreparative Example 2 to give3,4-dihydro-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran-4-ol.

¹ H-NMR(CDCl₃ /ppm) δ2.14(1H, dd, J=5.5 Hz, 14.5 Hz), 2.37(1H, dd, J=5.5Hz, 14.5 Hz), 3.36(3H, s), 3.40(3H, s), 3.35-3.65(5H, m), 4.80-4.87(1H,m), 6.93(1H, d, J=9.0 Hz), 8.06(1H, dd, J=2.7 Hz, 9.0 Hz), 8.34(1H, d,J=2.7 Hz).

PREPARATIVE EXAMPLE 9

Production of compound 5 (R¹ =nitro, R²,R³ =methoxymethyl)

3,4-Dihydro-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran-4-ol obtainedin Preparative Example 8 was treated in the same manner as inPreparative Example 3 to give2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran.

¹ H-NMR(CDCl₃ /ppm) δ3.39(6H, s), 3.55-3.63(4H, m), 5.80(1H, d, J=10.1Hz), 6.55(1H, d, J=10.1 Hz), 6.88(1H, d, J=8.9 Hz), 7.88(1H, d, J=2.7Hz), 8.02(1H, dd, J=2.7 Hz, 8.9 Hz).

PREPARATIVE EXAMPLE 10

Production of compound 6 (R¹ =nitro, R²,R³ =methoxymethyl)

2,2-bis(Methoxymethyl)-6-nitro-2H-1-benzopyran obtained in PreparativeExample 9 was treated in the same manner as in Preparative Example 4 togive3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran.

An optically active compound,(3S,4S)-3,4-epoxy-3,4-dihydro-6-nitro-2,2-bis(methoxymethyl)-2H-1-benzopyran,was obtained by oxidation using an Mn(III)-Salen (S,S) complex as inPreparative Example 5.

¹ H-NMR(CDCl₃ /ppm) δ3.26(3H, s), 3.48(3H, s), 3.57-3.76(4H, m),3.84(1H, d, J=3.0 Hz), 4.02(1H, d, J=3.0 Hz), 6.93(1H, d, J=9.0 Hz),8.14(1H, dd, J=3.0 Hz, 9.0 Hz), 8.30(1H, d, J=3.0 Hz).

PREPARATIVE EXAMPLE 11

Production of compound 3 (R¹ =fluoro, R²,R³ =methoxymethyl)

By treating 5-fluoro-2-hydroxyacetophenone in the same manner as inPreparative Example 1,6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-one wasobtained.

¹ H-NMR(CDCl₃ /ppm) δ2.89(2H, s), 3.36(6H, s), 3.56(4H, s),6.90-7.00(1H, m), 7.10-7.25(1H, m), 7.45-7.55(1H, m).

PREPARATIVE EXAMPLE 12

Production of compound 4 (R¹ =fluoro, R²,R³ =methoxymethyl)

6-Fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-oneobtained in Preparative Example 11 was treated in the same manner as inPreparative Example 2 to give6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-ol.

¹ H-NMR(CDCl₃ /ppm) δ2.06(1H, dd, J=5.5 Hz, 14.4 Hz), 2.28(1H, dd, J=5.5Hz, 14.4 Hz), 3.08(1H), 3.36(3H, s), 3.39(3H, s), 3.42(1H, d, J=10.0Hz), 3.48(1H, d, J=10.0 Hz), 3.57(1H, d, J=10.4 Hz), 3.75(1H, d, J=10.4Hz), 4.70-4.80(1H, m), 6.75-6.90(2H, m), 7.09(1H, dd, J=2.9 Hz, 8.8 Hz).

PREPARATIVE EXAMPLE 13

Production of compound 5 (R¹ =fluoro, R²,R³ =methoxymethyl)

6-Fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-olobtained in Preparative Example 12 was treated in the same manner as inPreparative Example 3 to give6-fluoro-2,2-bis(methoxymethyl)-2H-1-benzopyran.

¹ H-NMR(CDCl₃ /ppm) δ3.39(6H, s), 3.51-3.65(4H, m), 5.73(1H, d, J=10.0Hz), 6.44(1H, d, J=10.0 Hz), 6.67-6.70(1H, m), 6.76-6.80(2H, m).

PREPARATIVE EXAMPLE 14

Production of compound 6 (R¹ =fluoro, R²,R³ =methoxymethyl)

6-Fluoro-2,2-bis(methoxymethyl)-2H-1-benzopyran obtained in PreparativeExample 13 was treated in the same manner as in Preparative Example 4 togive3,4-epoxy-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran.

¹ H-NMR(CDCl₃ /ppm) δ3.30(3H, s), 3.48(3H, s), 3.52-3.77(5H, m),3.86(1H, d, J=6.0 Hz), 6.78-6.83(1H, m), 6.90-6.95(1H, m), 7.04-7.08(1H,m).

PREPARATIVE EXAMPLE 15

Production of compound 3 (R¹ =bromo, R²,R³ =methoxymethyl)

By treating 5-bromo-2-hydroxyacetophenone in the same manner as inPreparative Example 1,6-bromo-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-one wasobtained.

¹ H-NMR(CDCl₃ /ppm) δ2.89(2H, s), 3.36(6H, s), 3.55(4H, s), 6.89(1H, d,J=8.8 Hz), 7.53(1H, dd, J=2.5 Hz, 8.8 Hz), 7.95(1H, d, J=2.6 Hz).

PREPARATIVE EXAMPLE 16

Production of compound 4 (R¹ =bromo, R²,R³ =methoxymethyl)

6-Bromo-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-oneobtained in Preparative Example 15 was treated in the same manner as inPreparative Example 2 to give6-bromo-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-ol.

¹ H-NMR(CDCl₃ /ppm) δ2.08(1H, dd), 2.28(1H, dd), 3.20(1H), 3.36(3H, s),3.39(3H, s), 3.43(1H, d), 3.47(1H, d), 3.59(1H, d), 3.64(1H, d),4.73(1H, m), 6.76(1H, d), 7.25(1H, dd), 7.51(1H, d).

PREPARATIVE EXAMPLE 17

Production of compound 5 (R¹ =bromo, R²,R³ =methoxymethyl)

6-Bromo-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-ol obtainedin Preparative Example 16 was treated in the same manner as inPreparative Example 3 to give6-bromo-2,2-bis(methoxymethyl)-2H-1-benzopyran.

¹ H-NMR(CDCl₃ /ppm) δ3.39(6H, s), 3.54(2H, d), 3.60(2H, d), 5.71(1H, d),6.43(1H, d), 6.72(1H, d), 7.08(1H, d), 7.19(1H, dd).

PREPARATIVE EXAMPLE 18

Production of compound 6 (R¹ =bromo, R²,R³ =methoxymethyl)

6-Bromo-2,2-bis(methoxymethyl)-2H-1-benzopyran obtained in PreparativeExample 17 was treated in the same manner as in Preparative Example 5 togive 6.8 g of(3S,4S)-6-bromo-3,4-epoxy-3,4-dihydro-2,2-bis(methoxyethyl)-2H-1-benzopyran.

¹ H-NMR(CDCl₃ /ppm) δ3.29(3H, s), 3.48(3H, s), 3.47-3.87(6H, m),6.75(1H, d, J=8.8 Hz), 7.33(1H, dd, J=2.6 Hz, 8.8 Hz), 7.45(1H, d, J=2.6Hz).

PREPARATIVE EXAMPLE 19

Production of 3-amino-1-methyl-1,6-dihydropyridazine-6-thione

Pyridine (5 ml) and a Lawesson's reagent (970 mg, 2.4 mmol) were addedto 3-amino-1-methyl-1,6-dihydropyridazin-6-one (500 mg, 4 mmol) asdescribed in Journal of Medicinal Chemistry, 34 (10), 3074 (1991), andthe mixture was refluxed under heating for 5 hours. The reaction mixturewas concentrated and the residue obtained was subjected to silica gelcolumn chromatography (chloroform:methanol=100:1) to give 218 mg of3-amino-1-methyl-1,6-dihydropyridazine-6-thione.

¹ H-NMR(DMSO-d₆ /ppm) δ3.85(3H, s), 6.43(2H, br s), 6.72(1H, d, J=9.0Hz), 7.42(1H, d, J=9.0 Hz).

PREPARATIVE EXAMPLE 20

Production of 8-amino-1,2,3,4-tetrahydro-1,4,6-trimethylpyrazino2,3-d!pyridazin-5(6H)-one

Water (9 ml) and N,N'-dimethylethylenediamine (0.8 ml, 7.7 mmol) wereadded to 6-amino-4,5-dichloro-2-methyl-3(2H)-pyridazinone (500 mg, 2.6mmol) as described in Chemical Pharmaceutical Bulletin, 30, 832 (1982),and the mixture was refluxed under heating for 3 hours. The reactionmixture was concentrated, added with chloroform, washed with water andbrine and dried over anhydrous sodium sulfate. The solvent was distilledaway and the residue obtained was subjected to silica gel columnchromatography (chloroform:methanol=40:1) to give 448 mg of8-amino-1,2,3,4-tetrahydro-1,4,6-trimethylpyrazino2,3-d!pyridazin-5(6H)-one.

¹ H-NMR(DMSO-d₆ /ppm) δ2.53(3H, s), 2.73-2.76(2H, m), 2.96-2.99(2H, m),3.12(3H, s), 3.36(3H, s), 5.02(2H, br s).

PREPARATIVE EXAMPLE 21

Production of 3-amino-1,6-dihydropyridin-6-one

2-Hydroxy-5-nitropyridine (1 g) was dissolved in methanol (50 ml) andsubjected to hydrogenation in the presence of 10% palladium-carbon (600mg) at room temperature under 1 bar until the termination of hydrogenabsorption. The insoluble material was filtered off and the filtrate wasconcentrated to give 785 mg of the title compound.

¹ H-NMR(DMSO-d₆ /ppm) δ4.23(2H, br s), 6.22(1H, d, J=9 Hz), 6.73(1H, s),7.03(1H, d, J=9 Hz), 10.3-10.8(1H, br s).

PREPARATIVE EXAMPLE 22

Production of 1,6-dihydro-1-methyl-3-nitropyridin-6-one

Ethanol (70 ml), sodium hydroxide (856 mg) and methyl iodide (1.3 ml)were added to 2-hydroxy-5-nitropyridine (1 g) and the mixture wasrefluxed under heating for 5 hours. The reaction mixture wasconcentrated and added with chloroform. The insoluble material wasfiltered off and the filtrate was concentrated to give 1.85 g of thetitle compound.

¹ H-NMR(DMSO-d₆ /ppm) δ3.54(3H, s), 6.46(1H, d), 8.12(1H, dd),9.18(1H,d).

PREPARATIVE EXAMPLE 23

Production of 3-amino-1-methyl-1,6-dihydropyridin-6-one

Reduced iron (440 mg) and con. hydrochloric acid (0.02 ml) were added toa mixed solution of ethanol (6 ml) and water (6 ml), and the mixture washeated at 85° C. for 10 minutes.1,6-Dihydro-1-methyl-3-nitropyridin-6-one (500 mg) obtained inPreparative Example 22 was portionwise added, and the mixture wasstirred for 1 hour. A small amount of sodium carbonate was added to makethe mixture slightly alkaline. The mixture was filtered while heatingand the filtrate was concentrated to give 360 mg of the title compound.

¹ H-NMR(DMSO-d₆ /ppm) δ3.31(3H, s), 4.23(2H, br s), 6.23(1H, d, J=9 Hz),6.83(1H, d, J=3 Hz), 7.04(1H, dd, J=3 Hz, 9 Hz).

PREPARATIVE EXAMPLE 24

Production of 1,6-dihydro-3-hydroxy-1,4,5-trimethylpyridazin-6-one

2,3-Dimethylmaleic anhydride (2.5 g) was dissolved in acetic acid (45ml) and methylhydrazine (960 mg) was added. The mixture was stirred atroom temperature for 2 hours. Acetic acid was distilled away and theresidue obtained was recrystallized from dichloromethane-hexane to give2.6 g of the title compound.

¹ H-NMR(DMSO-d₆ /ppm) δ1.99(3H, s), 2.00(3H, s), 3.44(3H, s).

EXAMPLE 1

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

(3S,4S)-6-Cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran(4.18 g, 16 mmol) obtained in Preparative Example 5 and3-amino-1-methyl-1,6-dihydropyridazin-6-one (4.00 g, 32 mmol) asdescribed in Journal of Medicinal Chemistry, 34(10), 3074 (1991) weredissolved in dimethylformamide (40 ml) and 60% sodium hydride (1.92 g,48 mmol) was added at room temperature in an argon stream. After foamingcame to an end, the mixture was allowed to react at 60 ° C. for 2 hours.Ice-water was poured in the reaction mixture and the mixture wasextracted with chloroform. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent was distilledaway under reduced pressure to give a residue, which was purified bysilica gel column chromatography (ethyl acetate:ethanol=30:1-5:1) andrecrystallized from ethyl acetate to give 4.34 g of the title compound(56%, 99.5% ee).

EXAMPLE 2

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)oxy!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

(3S,4S)-6-Cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran(280 mg, 1.07 mmol) obtained in Preparative Example 5 and3-hydroxy-1-methyl-1,6-dihydropyridazin-6-one (142 mg, 1.13 mmol) asdescribed in Journal of Organic Chemistry, 36(22), 3372 (1971) weredissolved in ethanol (2.8 ml), and pyridine (0.13 ml) was added. Themixture was refluxed under heating for 8.5 hours. The solvent wasdistilled away and the residue was purified by silica gel columnchromatography (methanol:chloroform=1:99) to give 228 mg of the titlecompound (55%).

EXAMPLE 3

(-)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-3,4-dihydro-4-oxoquinazolin-2-ylthio!-2H-1-benzopyran-3-ol

A reaction mixture containing 2-mercapto-4(3H)quinazoline (161 mg),6-cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran(200 mg) and sodium carbonate (241 mg), in methanol (3 ml), was stirredat room temperature for 4 hours. The reaction mixture was dried overanhydrous magnesium sulfate and concentrated, and the residue waspurified by silica gel column chromatography (ethyl acetate:hexane:1:5)to give 241 mg of the title compound.

EXAMPLE 4

(-)-(3S,4R)-6-Cyano-4-(3-cyano-1H-indol-1-yl)-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

A reaction mixture containing6-cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran(300 mg), 3-cyanoindole (210 mg) and potassium carbonate (480 mg), indimethylformamide (3 ml), was stirred at 80° C. for 2.5 hours. Thereaction mixture was diluted with ethyl acetate, washed with water,1N-hydrochloric acid, an aqueous solution of sodium hydrogencarbonateand brine, dried over anhydrous sodium sulfate and concentrated, and theresidue was purified by silica gel column chromatography (ethylacetate:hexane=1:2) to give 298 mg of the title compound.

The following compounds of Examples 5 and 6 were obtained by treating inthe same manner as in any one of the above Examples.

EXAMPLE 5

(-)-(3S,4R)-4-(6-Chloro-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 6

(+)-(3S,4R)-6-Cyano-4-(3-formyl-1H-indol-1-yl)-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLES 7, 8

(-)-(3S,4R)-4-(6-Acetyloxy-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(Example 7)

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(Example 8)

Potassium acetate (380 mg) and acetic acid (6 ml) were added to(-)-(3S,4R)-4-(6-chloro-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1benzopyran-3-ol(750 mg) obtained in Example 5, and the mixture was refluxed withstirring for 5 hours. The reaction mixture was filtered and the residuewas washed with acetic acid. The residue obtained by removing thesolvent from the filtrate under reduced pressure was purified by silicagel column chromatography (ethyl acetate:ethanol=95:5), whereby(-)-(3S,4R)-4-(6-acetyloxy-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(180 mg, 22.6%) and (-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(500 mg, 69.9%) were obtained in the order of elution.

EXAMPLE 9

(-)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-3-(trans-β-nitro)vinyl-1H-indol-1-yl!-2H-1-benzopyran-3-ol

Ammonium acetate (22 mg) and nitromethane (3 ml) were added to(+)-(3S,4R)-6-cyano-4-(3-formyl-1H-indol-1-yl)-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(110 mg) obtained in Example 6, and the mixture was refluxed withstirring for 4 hours. Ammonium acetate (22 mg) and nitromethane (2 ml)were added, and the mixture was refluxed with stirring for 3 hours.Chloroform (200 ml) was added to the reaction mixture, and the mixturewas washed with water and dried over anhydrous sodium sulfate. Thesolvent was distilled away under reduced pressure and the residueobtained was separated and purified by silica gel column chromatography(ethyl acetate:hexane=3:7) to give 90 mg of the title compound (74.0%).

EXAMPLES 10, 11

(-)-(Z)-1-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-3-hydroxy-2H-1-benzopyran-4-yl!-1H-indol-3-carboxyaldehydoxime(Example 10)

(-)-(E)-1-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-3-hydroxy-2H-1-benzopyran-4-yl!-1H-indol-3-carboxyaldehydoxime(Example 11)

Hydroxylamine hydrochloride (260 mg) and pyridine (10 ml) were added to(+)-(3S,4R)-6-cyano-4-(3-formyl-1H-indol-1-yl)-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(700 mg) obtained in Example 6, and the mixture was stirred at roomtemperature for 5 hours. Chloroform was added to the reaction mixtureand the reaction mixture was washed with water and dried over anhydroussodium sulfate. The solvent was distilled away under reduced pressureand the residue obtained was separated and purified by silica gel columnchromatography (ethyl acetate:hexane=3:7), whereby (-)-(Z)-1-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-3-hydroxy-2H-1-benzopyran-4-yl!-1H-indol-3-carboxyaldehydoxime(293 mg, 40.4%) and (-)-(E)-1-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-3-hydroxy-2H-1-benzopyran-4-yl!-1H-indol-3-carboxyaldehydoxime(430 mg, 59.2%) were obtained in the order of elution.

The following compounds of Example 12 to Example 27 were obtained bytreating in the same manner as in any one of the above Examples.

EXAMPLE 12

Using methyl pyrazol-4-carboxylate obtained in Preparative Example 6,(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(4-methoxycarbonyl-1H-pyrazol-1-yl)-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olwas obtained.

EXAMPLE 13

(-)-(3S,4R)-6-Cyano-4-(1-ethyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 14

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-isopropyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 15

(-)-(3S,4R)-6-Cyano-4-(5-cyano-1H-indol-1-yl)-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 16

(+)-(3S,4R)-6-Cyano-3,4-dihydro-4-(3,4-dihydro-4-oxopyrimidin-3-yl)-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 17

(-)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-phenoxy-2H-1-benzopyran-3-ol

EXAMPLE 18

(±)-trans-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 19

(+)-(3S,4R)-6-Cyano-4-(2-cyanophenyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 20

(-)-(3S,4R)-6-Cyano-4-(4-cyanophenyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 21

(-)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(pyrimidin-2-yl)amino!-2H-1-benzopyran-3-ol

EXAMPLE 22

(+)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,4-dihydro-4-oxopyridin-1-yl)-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 23

(-)-(3S,4R)-4-(4-Amino-1,2-dihydro-2-oxopyrimidin-1-yl)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 24

(-)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(4-nitrophenoxy)-2H-1-benzopyran-3-ol

EXAMPLE 25

(+)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(1H-1,2,4-triazol-3-ylthio)-2H-1-benzopyran-3-ol

EXAMPLE 26

(+)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(1-methyl-1H-imidazol-2-ylthio)-2H-1-benzopyran-3-ol

EXAMPLE 27

(+)-(3S,4R)-4-(3-Amino-4H-1,2,4-triazol-4-yl)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 28

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol1/2 H₂ O

(3S,4S)-6-Cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran(56.75 g, 0.22 mol) obtained in Preparative Example 5 and3-amino-1-methyl-1,6-dihydropyridazin-6-one (30.00 g, 0.24 mol) asdescribed in Journal of Medicinal Chemistry, 34(10), 3074 (1991) weredissolved in dimethylformamide (300 ml), and 60% sodium hydride (17.4 g,0.44 mol) were added at room temperature in an argon stream. Afterfoaming came to an end, the mixture was allowed to react at 40° C. for 3hours. Ice-water was poured in the reaction mixture and the mixture wasextracted with chloroform. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent was distilledaway under reduced pressure to give a residue, which was purified bysilica gel column chromatography (ethyl acetate:ethanol=9:1),recrystallized from ethyl acetate, and recrystallized from water:ethanol(2:1) to give 32.0 g of the title compound (38%, 99.8% ee).

Elemental analysis Found:C (%) 57.59, H (%) 5.89, N (%) 14.11

Ultraviolet absorption spectrum (in methanol solution) λ_(MAX) :205.6 nm(ε=31000), 245.6 nm (ε=32000), 350 nm (ε=1800)

The compounds of the following Examples 29-33 were obtained by treatingin the same manner as in Example 1.

EXAMPLE 29

(3R,4R)-6-Cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyranobtained in Preparative Example 5 was treated in the same manner as inExample 1 to give (+)-(3R,4S)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 30

3,4-Epoxy-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyranobtained in Preparative Example 14 was treated in the same manner as inExample 1 to give trans-6-fluoro-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 31

(3S,4S)-6-Bromo-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyranobtained in Preparative Example 18 was treated in the same manner as inExample 1 to give (-)-(3S,4R)-6-bromo-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 32

3,4-Epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyranobtained in Preparative Example 10 was treated in the same manner as inExample 1 to give trans-4-(6-chloro-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran-3-ol.

EXAMPLE 33

3-Amino-6-pyridazinol described in Chemical Pharmaceutical Bulletin, 10,580 (1962) was treated in the same manner as in Example 1 to give(-)-(3S,4R)-4-(3-amino-1,6-dihydro-6-oxopyridazin-1-yl)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 34

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(3,4,7,8-tetrahydro-4,7-dimethyl-8-oxo-2H-pyridazino4,5-b!-1,4-oxazin-5-yl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

(3S,4S)-6-Cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran(87 mg, 0.33 mmol) obtained in Preparative Example 5 and5-amino-3,4-dihydro-4,7-dimethyl-2H-pyridazino4,5-b!-1,4-oxazin-8(7H)-one (98 mg, 0.5 mmol) as described in ChemicalPharmaceutical Bulletin, 30, 832 (1982) were dissolved indimethylformamide (3 ml), and potassium t-butoxide (112 mg, 1.0 mmol)was added under ice-cooling in a nitrogen stream. The mixture wasreacted for 10 minutes at room temperature and ice-water was added tothe reaction mixture. The resulting mixture was extracted withchloroform, and the organic layer was washed with saturated brine anddried over anhydrous sodium sulfate. The solvent was distilled awayunder reduced pressure to give a residue. The residue was purified bysilica gel column chromatography (chloroform: methanol=50:1-20:1) togive 126 mg of the title compound (83%).

The compounds of the following Examples 35-44 were obtained by treatingin the same manner as in Example 34.

EXAMPLE 35

8-Amino-3,4-dihydro-4,6-dimethyl-2H-pyridazino4,5-b!-1,4-oxazin-5(6H)-one as described in Chemical PharmaceuticalBulletin, 30, 832 (1982) was treated in the same manner as in Example 34to give (-)-(3S,4R)-6-cyano-3,4-dihydro-4-(3,4,5,6-tetrahydro-4,6-dimethyl-5-oxo-2H-pyridazino4,5-b!-1,4-oxazin-8-yl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 36

8-Amino-1,2,3,4-tetrahydro-1,4,6-trimethylpyrazino2,3-d!pyridazin-5(6H)-one obtained in Preparative Example 20 was treatedin the same manner as in Example 34 to give(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,2,3,4,5,6-hexahydro-1,4,6-trimethyl-5-oxopyrazino2,3-d!pyridazin-8-yl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 37

4-Amino-2-methylphthalazin-1(2H)-one described in Journal of theChemical Society; Perkin Transactions I, 2820 (1972) was treated in thesame manner as in Example 34 to give (-)-(3S,4R)-6-cyano-3,4-dihydro-4-(3,4-dihydro-3-methyl-4-oxophthalazin-1-yl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 38

3-Amino-1-methyl-1,6-dihydropyridazine-6-thione obtained in PreparativeExample 19 was treated in the same manner as in Example 34 to give(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-thioxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 39

(3S,4S)-3,4-Epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyranobtained in Preparative Example 10 was treated in the same manner as inExample 34 to give (+)-(3S,4R)-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran-3-ol.

EXAMPLE 40

3,4-Epoxy-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyranobtained in Preparative Example 14 was treated in the same manner as inExample 34 to give trans-4-(6-chloro-3-pyridazinyl)amino!-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 41

3,4-Epoxy-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyranobtained in Preparative Example 14 and4-amino-2-methylphthalazin-1(2H)-one described in Journal of theChemical Society; Perkin Transactions I, 2820 (1972) were treated in thesame manner as in Example 34 to give trans-6-fluoro-3,4-dihydro-4-(3,4-dihydro-3-methyl-4-oxophthalazin-1-yl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 42

(-)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(2-pyridylamino)-2H-1-benzopyran-3-ol

EXAMPLE 43

(-)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(3-pyridylamino)-2H-1-benzopyran-3-ol

EXAMPLE 44

(-)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(4-pyridylamino)-2H-1-benzopyran-3-ol

EXAMPLE 45

trans-4-(6-Chloro-3-pyridazinyl)amino!-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olobtained in Example 40 was treated in the same manner as in Example 8 togive trans-6-fluoro-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 46

(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

6-Cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran(380 mg) obtained in Preparative Example 4 was dissolved indimethylformamide (5 ml) and 3-amino-1-methyl-1,6-dihydropyridin-6-one(90 mg) obtained in Preparative Example 23 and triethylamine (1 ml) wereadded. The mixture was refluxed under heating for 30 hours. The reactionmixture was concentrated and the residue was purified by silica gelcolumn chromatography (chloroform:methanol=20:1) to give 125 mg of thetitle compound.

EXAMPLE 47

3-Amino-1,6-dihydropyridin-6-one obtained in Preparative Example 21 wastreated in the same manner as in Example 46 to give the followingcompound.

(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridyl)-amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 48

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-1-n-propyl-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(60 mg, 0.16 mmol) obtained in Example 8 and 1-bromopropane (0.017 ml,0.19 mmol) were dissolved in dimethylformamide (1.0 ml). Potassiumcarbonate (45 mg) was added and the mixture was reacted at 70° C. for 3hours. Water was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasdistilled away under reduced pressure to give a residue. The residue waspurified by silica gel column chromatography (methanol:chloroform=4:96)to give 33 mg of the title compound (50%).

The compounds of the following Examples 49-67 were obtained by thetreatment in the same manner as in Example 48.

EXAMPLE 49

(-)-(3S,4R)-6-Cyano-4-(1-cyclopropylmethyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 50

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methoxyethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 51

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-n-heptyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 52

(-)-(3S,4R)-4-(1-Allyl-1,6-dihydro-6-oxo-3-pyridazinyl)-amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 53

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-(methoxycarbonylmethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 54

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-(4-nitrophenyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 55

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-nitrophenyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 56

(3S,4R)-4-(1-Benzyloxycarbonylmethyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 57

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methylthioethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 58

(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-(dimethylamino)ethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 59

(-)-(3S,4R)-6-Cyano-4-(1-cyanomethyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 60

(-)-(3S,4R)-4-(1-Benzyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 61

(-)-(3S,4R)-4-(1-(2-(E)-Butenyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 62

(-)-(3S,4R)-6-Cyano-4-(1-(2-fluoroethyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 63

(-)-(3S,4R)-6-Cyano-4-(1-(2,2,2-trifluoroethyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 64

trans-6-Fluoro-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olobtained in Example 45 was treated in the same manner as in Example 48to give trans-6-fluoro-3,4-dihydro-4-(1,6-dihydro-6-oxo-1-n-propyl-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 65

trans-6-Fluoro-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olobtained in Example 45 was treated in the same manner as in Example 48to give trans-4-(1-(2-(E)-butenyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 66

trans-6-Fluoro-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olobtained in Example 45 was treated in the same manner as in Example 48to give trans-4-(1-allyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 67

(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olobtained in Example 47 was treated in the same manner as in Example 48to give (3S,4R)-6-cyano-4-(1-ethyl-1,6-dihydro-6-oxo-3-pyridyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLES 68, 69

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methylsulfonylethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(Example 68)

(+)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methylsulfinylethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(Example 69)

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methylthioethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(262 mg) obtained in Example 57 was dissolved in dichloromethane (20ml), and m-chloroperbenzoic acid (152 mg) was added under ice-cooling.The mixture was reacted for 30 minutes. The reaction mixture was pouredin a saturated aqueous solution of sodium hydrogen carbonate andextracted with chloroform. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent was distilledaway under reduced pressure to give a residue. The residue was purifiedby silica gel column chromatography (chloroform:methanol=30:1-20:1) togive 182 mg (65%) and 89 mg (33%) of the title compounds, respectively.

EXAMPLE 70

(-)-(3S,4R)-6-Cyano-4-(1-(2-cyanoethyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(150 mg, 0.40 mmol) obtained in Example 8 and acrylonitrile (0.055 ml,0.806 mmol) were dissolved in dimethylformamide (3 ml). Potassiumcarbonate (111 mg) was added and the mixture was reacted at 50° C.overnight. Water was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasdistilled away under reduced pressure and the residue was purified bysilica gel column chromatography (methanol:chloroform=1:30) to give 99mg of the title compound (58%).

The compounds of the following Examples 71-75 were obtained by treatingin the same manner as in Example 70.

EXAMPLE 71

Methyl acrylate was treated in the same manner as in EXAMPLE 70 to give(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methoxycarbonylethyl)-6-oxo-3-pyridazinyl)-amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 72

trans-6-Fluoro-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olobtained in Example 45 was treated in the same manner as in Example 70to give trans-4-(1-(2-cyanoethyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-fluoro-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 73

trans-6-Fluoro-3,4-dihydro-4-(1,6-dihydro-1-(2-methoxycarbonylethyl)-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

EXAMPLE 74

(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olobtained in Example 47 was treated in the same manner as in Example 70to give (3S,4R)-6-cyano-4-(1-(2-cyanoethyl)-1,6-dihydro-6-oxo-3-pyridyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 75

(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olobtained in Example 47 was treated in the same manner as in Example 70to give (3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-(2-methoxycarbonylethyl)-6-oxo-3-pyridyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 76

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-1-(2-nitroethyl)-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

Nitroethanol (0.79 ml) was dissolved in anhydrous dichloromethane. Underargon atmosphere, methanesulfonyl chloride (1.02 ml) and pyridine (1.07ml) were added and the mixture was stirred overnight at roomtemperature. Ice-water was added and the mixture was extracted withchloroform. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was distilled away underreduced pressure. The obtained residue (45 mg) and(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)-amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(50 mg) obtained in Example 8 were dissolved in dimethylformamide (1.5ml). Potassium carbonate (37 mg) was added and the mixture was refluxedunder heating at 100° C. for 4 hours. Ice-water was added and themixture was extracted with chloroform. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasdistilled away under reduced pressure and the residue obtained waspurified by silica gel column chromatography (chloroform:methanol=20:1)to give 42 mg of the title compound (70%).

EXAMPLE 77

(-)-(3S,4R)-6-Cyano-4-(1-(4-diethylamino-2-butyn-1-yl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(556 mg, 1.5 mmol) obtained in Example 8 and 1,4-dichloro-2-butyne (2.9ml, 30 mmol) were dissolved in dimethylformamide (10 ml). Potassiumcarbonate (413 mg) was added and the mixture was reacted at 120° C.overnight. Water was added to the reaction mixture and the mixture wasextracted with chloroform. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent was distilledaway under reduced pressure. The residue obtained was purified by silicagel column chromatography (methanol:chloroform=1:30) to give 171 mg ofcrude (3S,4R)-6-cyano-4-(1-(4-chloro-2-butyn-1-yl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.The compound was dissolved in dimethylformamide (3 ml), added withdiethylamine and stirred at 70° C. for 2.5 hours. Water was added andthe mixture was extracted with chloroform. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was distilled away under reduced pressure. The residue obtainedwas purified by silica gel column chromatography(chloroform:methanol=20:1) to give 71 mg of the title compound (38%).

EXAMPLE 78

(-)-(3S,4R)-4-(1-Carboxymethyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

(-)-(3S,4R)-4-(1-Benzyloxycarbonylmethyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol(186 mg) obtained in Example 56 was dissolved in methanol (5 ml) andsubjected to hydrogenation on 10% Pd--C (30 mg) at room temperatureunder 1 bar until the termination of hydrogen absorption. The insolublematerial was filtered off and the filtrate was concentrated. Chloroformwas added to the residue obtained and the mixture was made alkaline witha 0.1N aqueous solution of sodium hydroxide, and two layers werepartitioned. The aqueous layer was made acidic with 1N hydrochloric acidand extracted with chloroform. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasdistilled away under reduced pressure to give 45 mg of the titlecompound.

EXAMPLE 79

(-)-(3S,4R)-6-Cyano-4-(4-fluorophenyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol

(3S,4S)-6-Cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran(200 mg, 0.76 mmol) obtained in Preparative Example 5 andp-fluoroaniline (250 mg, 2.2 mmol) were dissolved in methanol (1 ml),and the mixture was stirred at room temperature for 3 days. Water wasadded to the reaction mixture and the mixture was extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate. Thesolvent was distilled away and the residue obtained was purified bysilica gel column chromatography (ethyl acetate:hexane=1:4) to give 243mg of the title compound (55%).

EXAMPLE 80

By treating in the same manner as in Example 79, (-)-(3S,4R)-6-cyano-4-(4-fluoro-3-methylphenyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olwas obtained.

EXAMPLE 81

(+)-2-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-3-hydroxy-2H-1-benzopyran-4-ylamino!-pyridine-N-oxide

(-)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(2-pyridylamino)-2H-1-benzopyran-3-ol(152 mg, 0.43 mmol) obtained in Example 42 was dissolved indichloromethane (5 ml), and m-chloroperbenzoic acid (150 mg, purity 80%)was added under ice-cooling. The mixture was stirred for 1.5 hours.Dichloromethane was added to the reaction mixture, and the mixture waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was distilled away and the residue obtained was purified bysilica gel column chromatography (methanol:chloroform=5:95) to give 94.5mg of the title compound (59%).

EXAMPLE 82

(-)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(3-pyridylamino)-2H-1-benzopyran-3-olobtained in Example 43 was treated in the same manner as in Example 81to give (+)-3-(3S,4R)-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-3-hydroxy-2H-1-benzopyran-4-ylamino!-pyridine-N-oxide.

EXAMPLE 83

By treating in the same manner as in Example 4,(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,2-dihydro-1-oxoisoquinolin-2-yl)-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olwas obtained.

EXAMPLE 84

By treating in the same manner as in Example 4,(+)-(3S,4R)-6-cyano-3,4-dihydro-4-(2,3-dihydro-3-oxoisoquinolin-2-yl)-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olwas obtained.

EXAMPLE 85

(3S,4S)-6-Cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyranobtained in Preparative Example 5 and2,3-dihydro-2-methylphthalazine-1,4-dione described in Journal of theChemical Society; Perkin Transactions I, 2820 (1972) and Journal of theChemical Society, 1710 (1960) were treated in the same manner as inExample 34 to give (-)-(3S,4R)-6-cyano-3,4-dihydro-4-(3,4-dihydro-3-methyl-4-oxophthaladin-1-yl)oxy!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 86

(3S,4S)-6-Cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyranobtained in Preparative Example 5 and1,6-dihydro-3-hydroxy-1,4,5-trimethylpyridazin-6-one obtained inPreparative Example 24 were treated in the same manner as in Example 2to give (-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1,4,5-trimethyl-6-oxo-3-pyridazinyl)oxy!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 87

(3S,4S)-6-Bromo-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyranobtained in Preparative Example 18 was treated in the same manner as inExample 2 to give (-)-(3S,4R)-6-bromo-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)oxy!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol.

EXAMPLE 88

(3S,4S)-3,4-Epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyranobtained in Preparative Example 10 and1,6-dihydro-3-hydroxy-1-methylpyridazin-6-one were treated in the samemanner as in Example 2 to give (-)-(3S,4R)-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)oxy!-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran-3-ol.

The properties of the compounds obtained in Examples 1 to 88 are shownin Tables 1 to 44.

                                      TABLE 1                                     __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________          ##STR4##         157.5˜158.5° C. (AcOEt)                                                    2220, 1658, 1574 KBr                                                               CD.sub.3 OD 3.37(3H,s), 3.46(3H,s),                                           .62(3H,s), 3.65-3.85(4H,m),                                                   4.16(1H,d,J=9.0Hz), 4.36(1H,d,J=9.0H                                          z), 5.09(1H,t,J=9.0Hz), 6.80-7.00(3H                                          ,m), 7.46(1H,dd,9.0Hz,1.0Hz),                                                 7.65(1H,dd,J=9.0Hz,1.0Hz).                                                                 386 (M.sup.+)                                                                     -126°                                                                  (c=0.49, MeOH)         2                                                                                   ##STR5##         1.37˜138° C. (-)                                                           2222, 1580, 1658 KBr                                                               DMSO-d.sub.6  3.24(3H,s),3.28(3H,s),                                           3.49(1H,d,J=10.3Hz), 3.55-3.65(2H,m                                          ),3.58(3H,s), 3.73(1H,d,J=10.3Hz),                                            4.20(1H,dd), 5.05(1H,d,J=6.0Hz),                                              6.06(1H,d,J=5.6Hz), 7.02(1H,d,J=9.8H                                          z), 7.04(1H,d,J=8.5Hz), 7.25                                                  (1H,d,J=9.8Hz), 7.69(1H,dd,J=8.5Hz,1                                          .8Hz), 7.80(1H,d,J=1.8Hz).                                                                 387 (M.sup.+)                                                                     -112.6°                                                                (c=1.0,                __________________________________________________________________________                                                           MeOH)              

                                      TABLE 2                                     __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________          ##STR6##         175.0˜176.5° C. (AcOEt)                                                    2225 1674 film                                                                     CDCl.sub.3  3.31(3H,s), 3.46(3H,s),                                           .74-3.89(4H,m), 4.48(1H,d),                                                   5.38(1H,d), 6.99(1H,d), 7.44-7.49(3H                                          ,m), 7.57(1H,d), 7.75(1H,t),                                                  7.98(1H,s), 8.27(1H,d).                                                                    439 (M.sup.+)                                                                     -103.8°                                                                (c=0.50, MeOH)         4                                                                                   ##STR7##         non- crystal- line solid                                                                2225 film                                                                          CDCl.sub.3  3.36(3H,s), 3.43(3H,s),                                           .55-4.12(4H,m), 4.58(1H,br s),                                                6.34-8.00(8H,m).                                                                           341 (M.sup.+)                                                                     -6.9°                                                                  (c=0.52,               __________________________________________________________________________                                                           MeOH)              

                                      TABLE 3                                     __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________          ##STR8##         197.0˜200.0° C. (CH.sub.2 Cl.sub.2 -                             Hexane)   2225 KBr                                                                           CDCl.sub.3  3.31(3H,s), 3.43(3H,s),                                           .65-3.85(4H,m), 4.23(1H,d,J=9.4Hz),                                           .71(1H,br,s), 5.48(1H,br                                                      t,J=9.0Hz), 5.61(1H,br d,J=8.1Hz)                                             6.87(1H,d,J=9.4Hz), 6.95(1H,d,J=8.5H                                          z) 7.22(1H,d,J=9.4Hz), 7.43(1H,                                               dd,J=8.5Hz,2.0Hz), 7.59(1H,d,J=2.0Hz                                          ).           390 (M.sup.+)                                                                     -104.0°                                                                (c=0.50, MeOH)         6                                                                                   ##STR9##         216.5˜217.5° C. (EtOH)                                                     2220, 1642 KBr                                                                     DMSO-d.sub.6  3.31(3H,s), 3.33(3H,s)                                          , 3.50-4.00(4H,m), 4.55(1H,br s),                                             5.60-8.70(10H,m), 9.97(1H,br                                                               406 (M.sup.+)                                                                     +30.6°                                                                 (c=1.02,                                                                      CHCl.sub.3)            __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________          ##STR10##        117.5˜120.0° C. (CH.sub.2 Cl.sub.2 -                             Hexane)   2226, 1749 KBr                                                                     CDCl.sub.3  2.05(3H,s), 3.34(3H,s),                                           .37(3H,s), 3.55-3.75(4H,m),                                                   4.75(1H,d,J=8.8Hz), 5.24(1H,t,J=8.8H                                          z), 5.52(1H,d,J=8.8Hz), 6.82(1H,d,J=                                          9.8Hz), 6.90(1H,d,J=9.8Hz),                                                   6.98(1H,d,J=8.5Hz),                                                           7.47(1H,dd,J=8.5 7.63(1H,d,J=2.0Hz).                                          N            414 (M.sup.+)                                                                     -10.2°                                                                 (c=0.50, MeOH)         8                                                                                   ##STR11##        138.5˜141.5° C. (CH.sub.2 Cl-                                              2225, 1673 KBr                                                                     CDCl.sub.3  3.24(3H,s), 3.25(3H,s),                                           .50-3.95(9H,m), 4.50-4.80(2H,m),                                              5.55(1H,br d,J=6.0Hz), 5.96(1H,br,s)                                          , 6.68(1H,d,J=9.8Hz), 6.90(1H,d,J=8.                                          5Hz), 6.97(1H,d,J=9.8Hz), 7.39(1H,dd                                          ,J=8.5,2.0Hz), 7.61(1                                                                      372 (M.sup.+)                                                                     -118.0°                                                                (c=0.50,               __________________________________________________________________________                                                           MeOH)              

                                      TABLE 5                                     __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________     9                                                                                  ##STR12##        non- crystal- line solid                                                                2224, 1621, 1492, 1315 KBr                                                         DMSO-d.sub.6  3.31(3H,s), 3.33(3H,s)                                          , 3.50-4.00(4H,m), 4.50(1H,br s),                                             5.50-8.60(11H,m).                                                                          449 (M.sup.+)                                                                     -55.2°                                                                 (c=0.54, MeOH)         10                                                                                  ##STR13##        non- crystal- line solid                                                                2226, 1612 KBr                                                                     DMSO-d.sub.6 (100° C.)                                                 3.27(3H,s), 3.37(3H,s), 3.60-3.95(4H                                          ,m), 4.53(1H,dd,J=9.9,6.2Hz),                                                 5.65(1H,d,J=6.2Hz), 5.73(1H,d,J=9.9H                                          z), 6.78(1H,s), 7.05-7.20(4H,m),                                              7.55-7.65(2H,m), 8.00-8.10(1H,m),                                             8.28(1H,s),  10.28(1H,s).                                                                  421 (M.sup.+)                                                                     -6.1°                                                                  (c=1.01,               __________________________________________________________________________                                                           MeOH)              

                                      TABLE 6                                     __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________    11                                                                                  ##STR14##        non- crystal- line solid                                                                2227, 1610 KBr                                                                     DMSO-d.sub.6 (100° C.)                                                 3.27(3H,s), 3.37(3H,s), 3.60-3.95(4H                                          ,m), 4.54(1H,dd,J=9.9,6.2Hz),                                                 5.67(1H,d,J=6.2Hz), 5.78(1H,d,J=9.9H                                          z), 6.77(1H,s), 7.00-7.25(4H,m),                                              7.55-7.65(1H,m), 7.77(1H,s),                                                  7.85-7.95(1H,m),  8.22(1H,br s),                                              10.98(1H,br s).                                                                            421 (M.sup.+)                                                                     -3.7°                                                                  (c=1.01, MeOH)         12                                                                                  ##STR15##        non- crystal- line solid                                                                2226.5, 1718.1 KBr                                                                 CDCl.sub.3  3.32(3H,s), 3.45(3H,s),                                           .6-4.0(4H,m), 3.85(3H,s), 4.65(1H,d)                                          , 5.56(1H,d), 6.88(1H,s), 6.99(1H,d)                                          , 7.46(1H,dd), 8.01(1H,s), 8.13(1H,s                                          ).           387 (M.sup.+)                                                                     -33.0°                                                                 (c=MeOH)               __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________    13                                                                                  ##STR16##        non- crystal- line solid                                                                2224, 1662 KBr                                                                     CDCl.sub.3  1.26(3H,t,J=7.2Hz),                                               3.35(3H,s), 3.46(3H,s), 3.65-3.85(4H                                          ,m), 3.99(2H,q,J=7.2Hz), 4.23(1H,d,J                                          =9.4Hz), 4.70(1H,br                                                           s), 5.05(1H,brt,J=8.3Hz), 6.84(2H,s)                                          , 6.95(1H,d,J=8.5Hz), 7.44(1H,dd,J=8                                          .5,2.0 Hz), 7.65(1H,d,J=2.0Hz).                                                            400 (M.sup.+)                                                                     -109.6°                                                                (c=0.95, MeOH)         14                                                                                  ##STR17##        non- crystal- line solid                                                                2224, 1662 KBr                                                                     CDCl.sub.3  1.04(3H,d,J=6.6Hz),                                               1.22(3H,d,J=6.6Hz), 3.34(3H,s),                                               3.45(3H,s), 3.65-3.85(4H,m),                                                  4.36(1H,d,J=9.6Hz), 4.83(1H,br                                                d,J=6.9Hz) 4.99(1H,br t,J=7.2Hz),                                             5.12(1H,septet,J=6.6Hz) 6.81(2H,s),                                           .96 (1H,d,J= 7.43(1H,dd,J=8.5,1.8Hz)                                          , 7.65(1H,d,J=1.8Hz).                                                                      414 (M.sup.+)                                                                     -57.6°                                                                 (c=1.02,               __________________________________________________________________________                                                           MeOH)              

                                      TABLE 8                                     __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________    15                                                                                  ##STR18##        non- crystal- line solid                                                                2224 KBr                                                                           CDCl.sub.3  3.38(3H,s), 3.43(3H,s),                                           .65-4.00(4H,m), 4.51(1H,br s),                                                5.40-8.00(9H,m).                                                                           403 (M.sup.+)                                                                     -0.5°                                                                  (c=0.98, MeOH)         16                                                                                  ##STR19##        non- crystal- line solid                                                                2228, 1625 KBr                                                                     CDCl.sub.3  3.42(6H,s), 3.58(4H,s),                                           .39(1H,d), 6.24(1H,br                                                         s), 6.92(1H,d), 7.45-7.53(3H,m),                                              8.29(1H,s), 11.06(1H,br                                                                    357 (M.sup.+)                                                                     +3.02°                                                                 (c=0.43,               __________________________________________________________________________                                                           MeOH)              

                                      TABLE 9                                     __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________    17                                                                                  ##STR20##        oily substance                                                                          2225 film                                                                          CDC.sub.3  3.34(6H,s), 3.39(4H,s),                                            4.42(1H,d), 5.31(1H,d), 6.98-7.10(4H                                          ,m), 7.32-7.37(2H,m), 7.48(1H,d),                                             7.64(1H,s).  355 (M.sup.+)                                                                     -58.6°                                                                 (c=0.5, MeOH)          18                                                                                  ##STR21##        244.5˜246° C. (EtOH- H.sub.2 O)                                            2222, 1568 KBr                                                                     DMSO-d.sub.6  3.23(3H,s), 3.28(3H,s)                                          , 3.43(3H,s), 3.49-3.70(4H,m),                                                4.09(1H,dd), 4.83(1H,t), 5.67(1H,d),                                           6.74-6.83(2H,m), 6.92-7.04(2H,m),                                            7.55-7.62(2H,m).                                                                           386 (M.sup.+)                                                                     0° (c=0.45,                                                            MeOH)                  __________________________________________________________________________

                                      TABLE 10                                    __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________    19                                                                                  ##STR22##        non- crystal- line solid                                                                2224 film                                                                          CDCl.sub.3  3.37(3H,s), 3.42(3H,s),                                           .58-3.92(4H,m), 4.23(1H,d),                                                   4.78-4.94(2H,m), 6.71-6.89(2H,m),                                             6.98(1H,d), 7.35-7.54(3H,m),                                                  7.59(1H,s).  379 (M.sup.+)                                                                     +32.4°                                                                 (c=0.51, MeOH)         20                                                                                  ##STR23##        non- crystal- line solid                                                                2222 KBr                                                                           CDCl.sub.3  3.37(3H,s), 3.42(3H,s),                                           .50(1H,d), 3.60-3.88(4H,m),                                                   4.17(1H,dd), 4.56(1H,d), 4.80(1H,t),                                           6.72(2H,d), 6.96(1H,d), 7.41-7.54(3                                          H,m), 7.57(1H,s).                                                                          379 (M.sup.+)                                                                     -105.6°                                                                (c=0.99,               __________________________________________________________________________                                                           MeOH)              

                                      TABLE 11                                    __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________    21                                                                                  ##STR24##        non- crystal- line solid                                                                2225 KBr                                                                           CDCl.sub.3  3.32(3H,s), 3.45(3H,s),                                           .68-3.87(4H,m), 4.21(1H,d),                                                   5.38(1H,t), 5.74(1H,d), 6.66(1H,t),                                           .98(1H,d), 7.46(1H,d), 7.66(1H,s),                                            8.27(2H,d).  356 (M.sup.+)                                                                     -4.2°                                                                  (c=0.64, CHCl.sub.3                                                           )                      22                                                                                  ##STR25##        non- crystal- line solid                                                                2226, 1639 KBr                                                                     CDCl.sub.3 (60° C.) 3.25(3H,s                                          ), 3.49(3H,s), 3.60(1H,d), 3.74(1H,s                                          ), 4.02(1H,d), 4.28(1H,d), 5.20(1H,d                                          ), 6.20(2H,d), 6.99(1H,s), 7.02(1H,d                                          ), 7.29(2H,br d), 7.46(1H,d).                                                              356 (M.sup.+)                                                                     +52.9°                                                                 (c=0.24,               __________________________________________________________________________                                                           MeOH)              

                                      TABLE 12                                    __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________    23                                                                                  ##STR26##        non- crystal- line solid                                                                2226, 1651 KBr                                                                     DMSO-d.sub.6 (90° C.)                                                  3.19(3H,s), 3.36(3H,s), 3.58(1H,d),                                           .63(2H,s) 3.73(1H,d), 4.45(1H,br                                              d), 5.53(1H,br s), 5.79(1H,d),                                                6.64(2H,br s), 6.97(1H,d), 7.06(1H,t                                          ), 7.35(1H,d), 7.51(1H,dd).                                                                372 (M.sup.+)                                                                     -37.2°                                                                 (c=0.50, MeOH)         24                                                                                  ##STR27##        non- crystal- line solid                                                                2227.6, 1590.8, 1343.1, 1252.7 KBr                                                 CDCl.sub.3  3.33(3H,s), 3.42(3H,s),                                           .61(2H,s), 3.76(1H,d), 3.9-4.1(2H,m)                                          , 4.48(1H,d), 5.50(1H,d), 7.01(1H,d)                                          , 7.19(2H,d), 7.54(1H,d), 7.58(1H,s)                                          , 8.27(2H,d).                                                                              400 (M.sup.+)                                                                     -62.4°                                                                 (c=1.12,               __________________________________________________________________________                                                           MeOH)              

                                      TABLE 13                                    __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________    25                                                                                  ##STR28##        non- crystal- line solid                                                                3434, 2224 KBr                                                                     CDCl.sub.3  3.27(3H,s), 3.48(3H,s),                                           .66-3.84(4H,m), 4.48(1H,d),                                                   4.73(1H,d), 6.96(1H,d), 7.45(1H,dd),                                           8.03(1H,s), 8.15(1H,s).                                                                   362 (M.sup.+)                                                                     +28.3°                                                                 (c=0.94, MeOH)         26                                                                                  ##STR29##        non- crystal- line solid                                                                2224 film                                                                          CDCl.sub.3  3.19(3H,s), 3.48(3H,s),                                           .73(3H,s), 3.62-3.83(4H,m),                                                   4.51(3H,d), 4.62(1H,d), 6.96(1H,d),                                           .00(1H,d), 7.02(1H,d), 7.46(1H,dd),                                           .99(1H,d).   375 (M.sup.+)                                                                     +3.0°                                                                  (c=1.05,               __________________________________________________________________________                                                           MeOH)              

                                      TABLE 14                                    __________________________________________________________________________    Ex. No.                                                                            Structural formula                                                                              m.p. (rec. from soln.)                                                                  IR cm.sup.-1                                                                       .sup.1 H NMR (δ)                                                                     MSm  α!.sub.D        __________________________________________________________________________    27                                                                                  ##STR30##        non- crystal- line solid                                                                2226.2 KBr                                                                         CDCl.sub.3  3.28(3H,s), 3.45(3H,s),                                           .57(1H,d), 3.65(1H,d), 3.80(1H,d),                                            3.89(1H,d), 4.26(2H,s), 4.54(2H,d),                                           .35(2H,d), 5.56(1H,br                                                         s), 7.05(1H,s), 7.44(1H,d),                                                   7.90(1H,s).  345 (M.sup.+)                                                                     +20.0°                                                                 (c=0.20, MeOH)         28                                                                                  ##STR31##        160.0˜161.0° C. (EtOH- H.sub.2                                             2221, 1655, 1572 KBr                                                               CD.sub.3 OD 3.32(3H,s), 3.38(3H,s),                                           .59(3H,s), 3.64(1H,d,J=10.7Hz),                                               3.65(1H,d,J=10.6Hz), 3.73(1H,d,J=10.                                          7Hz), 3.79(1H,d,J=10.6Hz), 4.25(1H,d                                          ,J=8.5Hz), 5.05(1H,d,J=8.5Hz),                                                6.84(1H,d,J=9.6Hz)                                                            , 6.95(1H,d,J=8.5Hz), 7.09(1H,d,J=9.                                          6Hz), 7.49(1H,m,J=8.5Hz,2.0Hz,                                                0.6Hz), 7.59(1H,m,J=2.0Hz,1.0Hz).                                                          386 (M.sup.+)                                                                     -126.6°                                                                (c=0.99,               __________________________________________________________________________                                                           MeOH)              

                                      TABLE 15                                    __________________________________________________________________________                          m.p. (rec.                                              Ex. No.                                                                           Structural formula                                                                              from soln.)                                                                          IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    29                                                                                 ##STR32##        159.0˜ 160.0° C. (EtOHH.sub.2 O)                                        3354, 2221, 1576 KBr                                                                DMSO-d.sub.6 3.22(3H, s), 3.27(3H, s),                                        3.42(3H, s), 3.50- 3.68(4H, m),                                               4.08(1H, dd, J=8.1Hz, 5.5Hz), 4.82(1H,                                        t, J=8.1Hz), 5.66(1H, d, J=5.5Hz),                                            6.74-6.84(2H, m), 6.92-7.04(2H, m),                                           7.54- 7.62(2H, m).  386 (M.sup.+)                                                                    +127.3°                                                                (c=1.045,                                                                     MeOH)               30                                                                                 ##STR33##        non- crystalline solid                                                               3300, 2926, 2816, 1662 film                                                         DMSO-d.sub.6 3.22(3H, s), 3.26(3H, s),                                        3.44(3H, s), 3.49- 3.64(4H, m),                                               4.05(1H, dd, J=4.5Hz, 9.0Hz), 4.73(1H,                                        t, J=15.0Hz), 5.48(1H, d, J=6.0Hz),                                           6.75-6.82(3H, m), 6.93-7.01(3H,                                                                   380 (M.sup.+)          __________________________________________________________________________

                                      TABLE 16                                    __________________________________________________________________________                           m.p. (rec.                                             Ex. No.                                                                           Structural formula from soln.)                                                                         IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    31                                                                                 ##STR34##         non- crystalline solid                                                              3342, 2928, 1579 KBr                                                                CDCl.sub.3  3.36(3H, s), 3.42(3H, s),                                         3.58(3H, s), 3.68 (1H, d, J=11.0Hz),                                          3.72(1H, d, J=10.6Hz),  3.76(1H, d,                                           J=10.6Hz), 3.84(1H, d, J=10.6Hz),                                             4.14(1H, dd. J=8.8Hz, 5.1Hz), 4.37(1H,                                        d, J= 5.5Hz), 4.88(1H, d, J=8.1Hz),                                           5.03(1H, t, J= 8.4Hz), 6.76-6.88(3H,                                          m), 7.26(1H, dd, J= 8.4Hz, 2.2Hz),                                            7.40(1H, d, J=2.2Hz).                                                                             339 (M.sup.+) 441                                                             (M.sup.+)                                                                        -86.2°                                                                 (c=1.02, MeOH)      32                                                                                 ##STR35##         non- crystalline solid                                                              3300, 2928, 1586, 1516, 1446                                                        CDCl.sub.3  3.31(3H, s), 3.44(3H, s),                                         3.69-3.85(4H, m), 4.25(1H, d,                                                 J=12.0Hz), 4.69(1H, br s), 5.31 (1H,                                          d, J=9.0Hz), 5.59(1H, t, J=9.0Hz),                                            6.90 (1H, d, J=9.0Hz), 6.99(1H, d,                                            J=9.0Hz), 7.24- 7.26(1H, m),                                                  8.04-8.08(1H, dd, J=3.0Hz, 9.0Hz),                                            8.20-8.21(1H, m).   411 (M.sup.+)          __________________________________________________________________________

                                      TABLE 17                                    __________________________________________________________________________                           m.p. (rec.                                             Ex. No.                                                                           Structural formula from soln.)                                                                         IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    33                                                                                 ##STR36##         186˜189° C. (CHCl.sub.3 -n- Hexane)                                    3353, 2932, 2225, 1611, 1560                                                        DMSO-d.sub.6  3.18(3H, s), 3.34(3H,                                           s), 3.53-3.73(4H, m), 4.53-4.60(1H,                                           m), 5.75(1H, d, J=6.0Hz), 5.86 (2H,                                           s), 6.08(1H, br s), 6.84(1H, d,                                               J=10.0Hz), 6.94-6.99(3H, m), 7.56(1H,                                         dd, J=8.5Hz, 1.5Hz).                                                                              372 (M.sup.+)                                                                    -51.5°                                                                 (c=1.31, MeOH)      34                                                                                 ##STR37##         non- crystalline solid                                                              2222, 1640, 1590 film                                                               DMSO-d.sub.6  2.68(3H, s), 3.01(2H,                                           m), 3.22(3H, s), 3.32 (3H, s),                                                3.40(3H, s), 3.56-3.67(4H, m), 4.12-                                          4.28(3H, m), 5.02(1H, t, J=8.7Hz),                                            5.58(1H, d, J=6.0Hz), 6.94(1H, d,                                             J=8.4Hz), 7.48-7.57 (2H,m).                                                                       457 (M.sup.+)                                                                    -90.5°                                                                 (c= 0.864,          __________________________________________________________________________                                                              MeOH)           

                                      TABLE 18                                    __________________________________________________________________________                           m.p. (rec.                                             Ex. No.                                                                           Structural formula from soln.)                                                                         IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    35                                                                                 ##STR38##         non- crystalline solid                                                              2223, 1631, 1594, 1520 film                                                         DMSO-d.sub.6  3.02(3H, s),                                                    3.12-3.15(2H, m), 3.20(3H, s),                                                3.29(3H, s), 3.38(3H, s),                                                     3.53-3.65(4H, m), 4.12-4.21(3H, m),                                           4.95(1H, t, J=9.0Hz), 5.58 (1H, d,                                            J=6.0Hz), 6.10(1H, d, J=9.0Hz), 6.93                                          (1H, d, J=9.0Hz), 7.47-7.59(2H,                                                                   457 (M.sup.+)                                                                    -65.5°                                                                 (c=0.86, MeOH)      36                                                                                 ##STR39##         non- crystalline solid                                                              2223, 1611, 1568 film                                                               DMSO-d.sub.6  2.56(3H, s),                                                    2.77-2.81(2H, m), 3.04-3.07(2H, m),                                           3.20(3H, s), 3.21(3H, s), 3.30(3H, s),                                        3.38 (3H, s), 3.54-3.65(4H, m),                                               4.19-4.24(1H, m), 4.94(1H, t,                                                 J=6.0Hz), 5.58(1H, d, J=6.0Hz),                                               5.73(1H, d, J=6.0Hz), 6.93(1H, d,                                             J=6.0Hz), 7.47-7.56(2H,                                                                           470 (M.sup.+)                                                                    -79.5°                                                                 (c=0.38,            __________________________________________________________________________                                                              MeOH)           

                                      TABLE 19                                    __________________________________________________________________________                           m.p. (rec.                                             Ex. No.                                                                           Structural formula from soln.)                                                                         IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    37                                                                                 ##STR40##         non- crystalline solid                                                              2223, 1636, 1577 KBr                                                                CDCl.sub.3  3.78(3H, s), 3.47(3H, s),                                         3.70(3H, s), 3.75- 3.86(4H, m),                                               4.31(1H, m), 4.43(1H, d, J= 3.5Hz),                                           4.96(1H, d, J=6.0Hz), 5.37(1H, m),                                            6.98(1H, d, J=6.4Hz), 7.46(1H, d,                                             J=6.4Hz), 7.60-7.85(4H, m),                                                   8.45-8.55(1H, m).   436 (M.sup.+)                                                                    -63.1°                                                                 (c=1.08, MeOH)      38                                                                                 ##STR41##         non- crystalline solid                                                              3445, 2927, 2224, 1490 KBr                                                          DMSO-d.sub.6  3.22(3H, s), 3.27(3H,                                           s), 3.50-3.69(4H, m), 3.88(3H, s),                                            4.09(1H, dd, J-=9.0Hz, 6.0Hz),                                                4.94(1H, t, J=9.0Hz), 5.76(1H, d,                                             J=6.0Hz), 6.80(1H, d, J=9.0Hz),                                               6.97(1H, d, J=9.0Hz), 7.35(1H, d,                                             J=6.0Hz), 7.46(1H, d, J=9.0Hz),                                               7.58-7.61 (2H, m).  402 (M.sup.+)                                                                    -101.9°                                                                (c=0.64,            __________________________________________________________________________                                                              MeOH)           

                                      TABLE 20                                    __________________________________________________________________________                           m.p. (rec.                                             Ex. No.                                                                           Structural formula from soln.)                                                                         IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    39                                                                                 ##STR42##         non- crystalline solid                                                              3300, 2954, 1573, 1514, 1430                                                        CDCl.sub.3  3.36(3H, s), 3.45(3H, s),                                         3.56(3H, s), 3.71-3.83(4H, m),                                                4.25(1H, br s), 4.60(1H, br s),                                               5.11(lH, br s), 6.80-6.98(3H, m), 8.03                                        1H, dd, J=8.5Hz, 2.1Hz), 8.22(1H, d,                                          J= 2.1Hz).          406 (M.sup.+)                                                                    +1.25°                                                                 (c= 0.16,                                                                     CHCl.sub.3)         40                                                                                 ##STR43##         non- crystalline solid                                                              3300, 2927, 1692, 1600, 1489                                                        CDCl.sub.3  3.34(3H, s), 3.44(3H, s),                                         3.69-3.83(4H, m), 4.18(1H, d,                                                 J=9.3Hz), 4.35(1H, br s), 5.21(1H, d,                                         J=8.2Hz), 5.40(1H, d, J=8.7Hz),                                               6.79-6.88 (3H, m), 6.96-7.00(1H, m),                                          7.20(1H, d, J= 9.3Hz).                                                                            383 (M.sup.+)          __________________________________________________________________________

                                      TABLE 21                                    __________________________________________________________________________                           m.p. (rec.                                             Ex. No.                                                                           Structural formula from soln.)                                                                         IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    41                                                                                 ##STR44##         125.5˜ 127.5° C. (Et.sub.2 O)                                          3346, 2927, 2815, 1633 film                                                         DMSO-d.sub.6  3.23(3H, s),3.31(3H, s),                                        3.55(3H, s), 3.57- 3.69(4H, m),                                               4.30(1H, dd, J=6.0Hz, 9.0Hz), 5.14(1H,                                        t, J=9.0Hz), 5.50(1H, d, J=6.0Hz),                                            6.79-6.84(1H, m), 6.93-6.98(2H, m),                                           7.05 (1H, d, J=9.0Hz), 7.80-7.89(2H,                                          m), 8.25- 8.27(2H, m)                                                                             430 (M.sup.+)          42                                                                                 ##STR45##         non- crystalline solid                                                              2228, 1610 KBr                                                                      CDCl.sub.3  3.30(3H, s), 3.47(3H, s),                                         3.70-3.90(4H, m), 4.18(1H, d,                                                 J=9.2Hz), 4.66(1H, d, J=7.3Hz),                                               5.28(1H, dd, J=7.3Hz, 9.2Hz), 6.60(1H,                                        d, J= 8.4Hz), 6.65-6.75(1H, m),                                               7.00(1H, d, J=8.4 Hz), 7.40-7.60(2H,                                          m), 7.69(1H, s), 8.05(1H, d,                                                                      355 (M.sup.+)                                                                    -73.2°                                                                 (c=0.97,            __________________________________________________________________________                                                              MeOH)           

                                      TABLE 22                                    __________________________________________________________________________                           m.p. (rec.                                             Ex. No.                                                                           Structural formula from soln.)                                                                         IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    43                                                                                 ##STR46##         non- crystalline solid                                                              2223 KBr                                                                            CDCl.sub.3  3.35(3H, s), 3.44(3H, s),                                         3.68(1H, d, J=8.1Hz), 3.71(1H, d,                                             J=8.1Hz), 3.79(1H, d, J=7.9Hz),                                               3.83(1H, d, J=7.9Hz), 4.15-4.25(2H,                                           m), 4.65- 4.75(1H, m), 6.85-6.92(1H,                                          m), 6.97(1H, d, J= 6.4Hz),                                                    7.00-7.08(1H, m), 7.45(1H, d, J=6.4                                           Hz), 7.63(1H, s), 7.90-7.98(2H,                                                                   355 (M.sup.+)                                                                    -26.2°                                                                 (c=0.37, MeOH)      44                                                                                 ##STR47##         195.8˜ 197.9° C. (MeOH)                                                2223, 1606 KBr                                                                      DMSO-d.sub.6  3.24(3H, s), 3.28(3H,                                           s), 3.53(1H, d, J=8.0 Hz), 3.56(1H, d,                                        J=8.0Hz), 3.63(1H, d, J=8.0 Hz),                                              3.74(1H, d, J=8.0Hz), 4.01(1H, dd, J=                                         3.7Hz, 5.9Hz), 4.67(1H, dd, J=5.9Hz,                                          6.2Hz), 5.80(1H, d, J=3.7Hz), 6.62(1H,                                        d, J=4.5Hz), 6.85(1H, d, J=6.2Hz),                                            6.99(1H, d, J =6.5Hz), 7.49(1H, d,                                            J=1.5Hz), 7.61(1H, dd, J=1.5Hz,                                               6.5Hz), 8.06(1H, d, J=4.5Hz).                                                                     355 (M.sup.+)                                                                    -64.7°                                                                 (c=0.38,            __________________________________________________________________________                                                              MeOH)           

                                      TABLE 23                                    __________________________________________________________________________                          m.p. (rec.                                              Ex. No.                                                                           Structural formula                                                                              from soln.)                                                                          IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    45                                                                                 ##STR48##        non- crystalline solid                                                               3280, 2932, 1674, 1592, 1567                                                        CDCl.sub.3 3.30(3H, s), 3.34(3H, s),                                          3.67-3.88(4H, m), 4.25(1H, d,                                                 J=7.5Hz), 4.42(1H, br, s), 4.69 (1H,                                          d, J=8.0Hz), 4.87(1H, t, J=8.0Hz),                                            6.79- 6.90(4H, m), 6.96-7.01(1H, m),                                          10.31(1H, br s).    365 (M.sup.+)          46                                                                                 ##STR49##        non- crystalline solid                                                               3316, 2925, 2224, 1668, 1568                                                        DMSO-d.sub.6 3.23(3H, s), 3.25(3H, s),                                        3.37(3H, s), 3.50- 3.68(4H, m),                                               3.95(1H, d, J=6.0Hz), 4.18(1H, d,                                             J=6.0Hz), 6.36(1H, d, J=9.0Hz),                                               6.97(1H, d, J=9.0Hz), 7.00(1H, d,                                             J=3.0Hz), 7.20(1H, dd, J=3.0Hz,                                               9.0Hz), 7.58-7.66(2H,                                                                             385 (M.sup.+)          __________________________________________________________________________

                                      TABLE 24                                    __________________________________________________________________________                           m.p. (rec.                                             Ex. No.                                                                           Structural formula from soln.)                                                                         IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    47                                                                                ##STR50##          non- crystalline solid                                                              2224, 1666, 1606, 1551 film                                                         DMSO-d.sub.6  3.20(3H, s), 3.25(3H,                                           s), 3.49-3.69(4H, m), 3.97(1H, d,                                             J=9.0Hz), 4.20(1H, t, J=6.0Hz),                                               5.30(1H, d, J=9.0Hz), 6.29(1H, d,                                             J=9.0Hz), 6.72(1H, d, J=3.0Hz),                                               6.96(1H, d, J=9.0Hz), 7.19(1H, dd,                                            J=9.0Hz, 3.0Hz), 7.58-7.65(2H,                                                                    371  (M.sup.+)         48                                                                                ##STR51##          non- crystalline solid                                                              3318, 2933, 2224, 1661 film                                                         DMSO-d.sub.6  0.75(3H, t, J=7.5Hz),                                           1.49-1.61(2H, m), 3.20 (3H, s),                                               3.28(3H, s), 3.51-3.66(4H, m), 3.73                                           (2H, t, J=7.5Hz), 4.22(1H, dd,                                                J=6.0Hz,  6.0Hz), 4.73(1H, t,                                                 J=6.0Hz), 5.64(1H, d, J= 6.0Hz),                                              6.76(1H, d, J=9.0Hz), 6.86(1H, d, J=                                          6.0Hz), 6.94-7.01 (2H, m),                                                    7.55-7.58(2H, m).   415 (M.sup.+)                                                                    -112.8°                                                                (c=0.83,            __________________________________________________________________________                                                              MeOH)           

                                      TABLE 25                                    __________________________________________________________________________    Ex.                    m.p. (rec.                                             No.                                                                              Structural formula  from soln.)                                                                         IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    49                                                                                ##STR52##          non- crystalline solid                                                              3316, 3009, 2931, 2224, 1660                                                        DMSO-d.sub.6  0.18-0.42(4H, m),                                               1.04-1.15(1H, m), 3.20(3H, s),                                                3.29(3H, s), 3.53-3.72(6H, m),                                                4.23(1H, dd, J=5.6Hz, 5.5Hz), 4.76(1H,                                        t, J= 7.8Hz), 5.62(1H, d, J=5.5Hz),                                           6.77(1H, d, J= 9.7Hz), 6.85(1H, d,                                            J=7.2Hz), 6.94-7.03(2H, m), 7.55                                              -7.59(2H, m).       427 (M.sup.+)                                                                    -99.4°                                                                 (c=0.66, MeOH)      50                                                                                ##STR53##          non- crystalline solid                                                              2223, 1664, 1578 KBr                                                                CDCl.sub.3  3.34(3H, s), 3.35(3H, s),                                         3.45(3H, s), 3.62- 3.90(6H, m),                                               4.05-4.30(3H, m), 4.50-4.70 (1H, m),                                          5.00-5.10(1H, m), 6.87(2H, s), 6.96                                           (1H, d, J=8.4Hz), 7.45(1H, d,                                                 J=8.4Hz), 7.67 (1H, s).                                                                           430 (M.sup.+)                                                                    -110.1°                                                                (c=0.82,            __________________________________________________________________________                                                              MeOH)           

                                      TABLE 26                                    __________________________________________________________________________                             m.p. (rec.                                           Ex. No.                                                                           Structural formula   from soln.)                                                                         IR cm.sup.-1                                                                      .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    51                                                                                 ##STR54##           non- crystalline solid                                                              2224, 1663, 1577 KBr                                                              CDCl.sub.3  0.75-0.95(3H, m),                                                 1.15-1.40(10H, m), 3.34 (3H, s),                                              3.44(3H, s), 3.65-4.00(8H, m), 4.18-                                          4.25(1H, m), 4.50-4.70(1H, m),                                                5.00-5.10(1, m), 6.84(2H, s), 6.93(1H,                                        d, J=8.5Hz), 7.43 (1H, d, J=8.5Hz),                                           7.64(1H, s).        470 (M.sup.+)                                                                    -103.1°                                                                (c=0.48, MeOH)      52                                                                                 ##STR55##           non- crystalline solid                                                              2224, 1664, 1578 KBr                                                              CDCl.sub.3  3.35(3H, s), 3.46(3H, s),                                         3.65-3.85(4H, m), 4.03-4.04(1H, m),                                           4.16-4.24(1H, m), 4.53- 4.70(3H, m),                                          5.00-5.24(3H, m), 5.80-5.95(1H, m),                                           6.86(2H, s), 6.95(1H, d, J=9.0Hz),                                            7.45 (1H, d, J=9.0Hz), 7.66(1H,                                                                   412 (M.sup.+)                                                                    -131.3°                                                                (c=0.77,            __________________________________________________________________________                                                              MeOH)           

                                      TABLE 27                                    __________________________________________________________________________    Ex.                      m.p. (rec.                                           No.                                                                              Structural formula    from soln.)                                                                         IR cm.sup.-1                                                                      .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    53                                                                                ##STR56##            non- crystalline solid                                                              3378, 2928, 2225, 1752, 1670, 1582, 1511                                      KBr DMSO-d.sub.6  3.20(3H, s), 3.27(3H,                                           s), 3.51-3.65(4H, m), 3.65(3H, s),                                            4.07(1H, dd, J=9.0Hz,                                                         6.0Hz), 4.50-4.69(2H, m), 4.76(1H, t,                                         J=9.0Hz), 5.67 (1H, d, J=6.0Hz),                                              6.84(1H, d, J=9.0Hz), 6.92- 6.96(2H,                                          m), 7.07(1H, d, J=12.0Hz), 7.56-7.59                                          (2H, m).            444 (M.sup.+)                                                                    -127°                                                                  (c=0.80, MeOH)      54                                                                                ##STR57##            164˜ 169° C. (CHCl.sub.3 - n-Hexane)                             O     3374, 2926, 2223, 1611, 1518 KBr                                                  DMSO-d.sub.6  3.20(3H, s), 3.26(3H,                                           s), 3.52-3.69(4H, m), 4.21-4.25(1H,                                           m), 4.93(1H, t, J=9.0Hz), 5.76 (1H, t,                                        J=6.0Hz), 6.95-7.00(2H, m), 7.18(1H,                                          d, J=6.0Hz), 7.29(1H, d, J=9.0Hz),                                            7.59(1H, d, J=6.0Hz), 7.68(1H, br s),                                         8.00(2H, d, J= 9.0 Hz), 8.23(2H, d,                                           J=9.0Hz).           493 (M.sup.+)                                                                    -83.1°                                                                 (c=0.85,            __________________________________________________________________________                                                              MeOH)           

                                      TABLE 28                                    __________________________________________________________________________                             m.p. (rec.                                           Ex. No.                                                                           Structural formula   from soln.)                                                                         IR cm.sup.-1                                                                      .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    55                                                                                 ##STR58##           165˜ 171° C. (CHCl.sub.3 - n-Hexane)                             O     3422, 2926, 2224, 1610, 1534 KBr                                                  DMSO-d.sub.6  3.16(3H, s), 3.28(3H,                                           s), 3.50-3.64(4H, m), 4.13(1H, dd,                                            J=5.5Hz, 9.0Hz), 4.82(1H, t, J=                                               9.0Hz), 5.70(1H, d, J=5.5Hz),                                                 6.90-6.96(2H, m), 7.14(1H, d,                                                 J=8.0Hz), 7.19(1H, d, J=10.0 Hz),                                             7.57-7.62(4H, m),7.77-7.82(1H, m),                                            7.98(1H, dd, J=8.0Hz,                                                                             493 (M.sup.+)                                                                    -174.5°                                                                (c=0.98, MeOH)      56                                                                                 ##STR59##           non- crystalline solid                                                                  DMSO-d.sub.6  3.19(3H, s), 3.26(3H,                                           s), 3.51-3.64(4H, m), 4.05-4.10(1H,                                           m), 4.56-4.61(3H, m), 5.11- 5.20(2H,                                          m), 5.67(1H, d, J=6.0Hz), 6.85(1H, d,                                         J=9.0Hz), 6.92-6.97(2H, m), 7.08(1H,                                          d, J=9.0Hz), 7.32-7.35(5H, m),                                                7.56-7.59(2H, m).   520 (M.sup.+)          __________________________________________________________________________

                                      TABLE 29                                    __________________________________________________________________________    Ex.                    m.p. (rec.                                             No.                                                                              Structural formula  from soln.)                                                                         IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                            MSm                                                                               α!.sub.D     __________________________________________________________________________    57                                                                                ##STR60##          non- crystalline solid                                                              3342, 2927, 2223, 1663, 1577                                                        DMSO-d.sub.6  1.99(3H, s), 2.64(2H, t,                                        J=6.0Hz), 3.19(3H, s), 3.28(3H, s),                                           3.51-3.66(4H, m), 3.88-4.01(2H, m),                                           4.23(1H, dd, J=9.0Hz, 6.0Hz), 4.73(1H,                                        t, J=9.0Hz), 5.67(1H, d, J=6.0Hz),                                            6.78(1H, d, J=9.0Hz), 6.92-6.96(2H,                                           m), 7.01(1H, d, J= 9.0Hz), 7.                                                 54-7.57(2H, m).     446 (M.sup.+)                                                                    -105.2°                                                                (c=0.56, MeOH)      58                                                                                ##STR61##          non- crystalline solid                                                              3448, 2224, 1578 KBr                                                                DMSO-d.sub.6  2.11(6H, s),                                                    2.37-2.50(2H, m), 3.19(3H, s),                                                3.28(3H, s), 3.51-3.66(4H, m),                                                3.82-3.88(2H, m), 4.20(1H, dd,                                                J=9.0Hz, 6.0Hz), 4.75(1H, t, J=9.0Hz),                                        5.66(1H, d, J=6.0Hz), 6.75(1H, d,                                             J=12.0Hz), 6.88(1H, d, J=6.0Hz),                                              6.94-6.97 (1H, m), 7.00(1H, d,                                                J=9.0Hz), 7.55 -7.58(2H, m).                                                                      443 (M.sup.+)          __________________________________________________________________________

                                      TABLE 30                                    __________________________________________________________________________                              m.p. (rec.                                          Ex. No.                                                                            Structural formula   from soln.)                                                                          IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                       MSm                                                                               α!.sub.D      __________________________________________________________________________    59                                                                                  ##STR62##           non- crystalline solid                                                               2362, 2225, 1670, 1589 film                                                         DMSO-d.sub.6  3.22(3H, s),                                                    3.27(3H, s), 3.51-3.67(4H, m),                                                4.05-4.10(1H, m), 4.83-4.99(3H,                                               m), 5.70(1H, d, J=6.0Hz), 6.89(1H,                                            d, J=9.0Hz), 6.97(1H, d, J=9.0Hz),                                            .08-7.11(2H, m), 7.57-7.60(2H,                                                               411                                                                              -80.0° (c                                                              = 1.05, MeOH)        60                                                                                  ##STR63##           non- crystalline solid                                                               3375, 2928, 2224, 1664, 1577 KBr                                                    CDCl.sub.3  3.32(3H, s), 3.44(3H,                                             s), 3.65-3.85(4H, m), 4.23(1H, dd,                                            =6.0Hz, 3.0Hz), 4.54(1H, br s),                                               4.76(1H, d, J=6.0Hz), 4.90-5.10(4H,                                            m), 6.47(1H, d, J=9.0Hz),                                                    6.68(1H, d, J=9.0Hz), 6.95(1H, d,                                             J=9.0Hz), 7.25 -7.38(6H, m),                                                  7.41(1H, dd, J=8.5Hz, 3.0Hz),                                                 7.54(1H, br s).                                                                              426 (M.sup.+)                                                                    -122.9°                                                                (c = 1.00,           __________________________________________________________________________                                                             MeOH)            

                                      TABLE 31                                    __________________________________________________________________________                              m.p. (rec.                                          Ex. No.                                                                            Structural formula   from soln.)                                                                          IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                       MSm                                                                               α!.sub.D      __________________________________________________________________________    61                                                                                  ##STR64##           non- crystalline solid                                                               3315, 2922, 2223, 1661, 1608, 1574                                                  CDCl.sub.3  1.65-1.74(3H, m),                                                 3.34(3H, s), 3.46(3H,                                                         s), 3.70-3.82(4H,                                                             m), 4.21-4.23(2H, m), 4.22(1H, d,                                             J=6.0Hz), 4.61-4.68(1H, m),                                                   4.85-5.18(1H, m), 5.47-5.76(2H,                                               m), 6.77-6.89(2H, m), 6.96(1H, d,                                             J=9.0 Hz), 7.44(1H, d, J=9.0Hz),                                              7.66(1H, s).   426 (M.sup.+)                                                                    -134.5°                                                                (c = 0.47,                                                                    MeOH)                62                                                                                  ##STR65##           non- crystalline solid                                                               2224, 1789, 1665, 1574 film                                                         DMSO-d.sub.6  3.21(3H, s),                                                    3.29(3H, s), 3.53-3.67(4H, m),                                                4.05-4.21(3H, m), 4.52-4.80(3H,                                               m), 5.65(1H, d, J=4.2Hz), 6.81(1H,                                            d, J=7.4Hz), 6.93-6.97(2H, m),                                                7.04(1H, d, J=7.1Hz), 7.56-7.58(2H,                                            m).           418                                                                              -89.5° (c                                                              = 0.41, MeOH)        __________________________________________________________________________

                                      TABLE 32                                    __________________________________________________________________________                            m.p. (rec.                                            Ex. No.                                                                            Structural formula from soln.)                                                                            IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                       MSm                                                                               α!.sub.D      __________________________________________________________________________    63                                                                                  ##STR66##         non- crystalline solid                                                                 2225, 1673, 1593 film                                                               DMSO-d.sub.6  3.20(3H, s),                                                    3.29(3H, s), 3.53-3.65(4H, m),                                                4.11-4.15(1H, m), 4.55-4.70(2H,                                               m), 4.81(1H, t, J=6.2Hz), 5.64(1H,                                            d, J=4.1Hz), 6.89(1H, d, J=7.3Hz),                                            .96(1H, d, J=6.8Hz), 7.03(1H, d,                                              J=5.7Hz), 7.11(1H,  d, J=7.3Hz),                                              7.56-7.58(2H, m).                                                                            454 (M.sup.+)                                                                    -86.4° (c                                                              = 0.14, MeOH)        64                                                                                  ##STR67##         180.0˜182.0° C. (Et.sub.2 O)                                              3315, 2933, 1661, 1574, 1504 film                                                   DMSO-d.sub.6  0.78(3H, t,                                                     J=7.5Hz), 1.59(2H, dd, J=6.0Hz,                                               9.0Hz), 3.21(3H, s), 3.27(3H, s),                                             3.50-3.64(4H, m), 3.75(2H, t,                                                 J=6.0Hz), 4.13-4.18(1H, m),                                                   4.67(1H, t, J=7.5Hz), 5.46(1H, d,                                             J=6.0Hz), 6.73-6.82(3H, m ),                                                  6.92-7.00(3H, m).                                                                            408 (M.sup.+)           __________________________________________________________________________

                                      TABLE 33                                    __________________________________________________________________________                             m.p. (rec.                                           Ex. No.                                                                            Structural formula  from soln.)                                                                            IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                       MSm  α!.sub.D    __________________________________________________________________________    65                                                                                  ##STR68##          145.5˜146.5° C. (Et.sub.2 O)                                              3315, 2921, 1661, 1573, 1488 film                                                   CDCl.sub.3  1.61-1.77(3H, m),                                                 3.36(3H, s), 3.47(3H, s),                                                     3.69-3.83(4H, m), 3.91-3.99(1H,                                               m), 4.13-4.19(1H,                                                             m), 4.45-4.65(3H, m), 4.97(1H, t,                                             J=7.5Hz), 5.56-5.75(2H, m),                                                   6.78-6.91(4H, m),  7.03-7.07(1H,                                              m).            419 (M.sup.+)          66                                                                                  ##STR69##          non- crystalline solid                                                                 3312, 2926, 1663, 1577, 1509, 1489                                                  DMSO-d.sub.6  3.21(3H, s),                                                    3.28(3H, s), 3.51-3.63(4H, m),                                                4.12(1H, dd, J=4.1Hz, 6.4Hz),                                                 4.34-4.49(2H, m), 4.70(1H, t,                                                 J=9.0Hz), 5.05-5.12(2H, m),                                                   5.43(1H, d, J=4.1Hz), 5.83-5.90(1H                                            , m), 6.76-6.83(3H, m),                                                       6.93-6.97(2H, m), 7.02(1H, d,                                                 J=7.3Hz).      405 (M.sup.+)          __________________________________________________________________________

                                      TABLE 34                                    __________________________________________________________________________                              m.p. (rec.                                          Ex. No.                                                                            Structural formula   from soln.)                                                                          IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                       MSm                                                                               α!.sub.D      __________________________________________________________________________    67                                                                                  ##STR70##           non- crystalline solid                                                               3314, 2931, 2224, 1667, 1608, 1567, 1558                                      ilm   DMSO-d.sub.6  1.19(3H, t,                                                     J=5.2Hz), 3.24(3H, s), 3.27(3H,                                               s), 3.53-3.69(4H,                                                             m), 3.79-3.81(2H, m), 3.98(1H, d,                                             J=5.6Hz), 4.21(1H, d, J=5.6Hz),                                               5.26(1H, br s), 5.64(1H, br s),                                               6.33(1H, d, J=7.2Hz) , 6.92(1H, d,                                            J=2.1Hz), 6.97(1H, d, J=6.6Hz),                                               7.20(1H, dd, J=7.2Hz, 2.1Hz),                                                 7.59-7.69(2H, m).                                                                            399 (M.sup.+)           68                                                                                  ##STR71##           non- crystalline solid                                                               3384, 2927, 2224, 1664, 1578 KBr                                                    DMSO-d.sub.6  2.95(3H, s),                                                    3.22(3H, s), 3.41(2H, t, J=7.0Hz),                                            .53-3.69(4H, m), 4.16-4.23(2H, m),                                            .82(1H, t, J=8.0Hz), 5.65(1H, d,                                              J=6.0Hz), 6.81(1H, d, J=10.0Hz),                                              6.96(2H, d, J=8.0Hz), 7.04(1H, d,                                             J=10.0Hz),  7.56-7.59(2H,                                                                    478 (M.sup.+)                                                                    -42.2° (c                                                              = 1.09, MeOH)        __________________________________________________________________________

                                      TABLE 35                                    __________________________________________________________________________                              m.p. (rec.                                          Ex. No.                                                                            Structural formula   from soln.)                                                                          IR cm.sup.-1                                                                         .sup.1 H NMR (δ)                                                                    MSm  α!.sub.D       __________________________________________________________________________    69                                                                                  ##STR72##           non- crystalline solid                                                               3299, 2924, 2223, 1664, 1578 KBr                                                     DMSO-d.sub.6  2.52(3H, s),                                                    2.93-3.07(2H, m), 3.23(3H, s),                                                3.29(3H, s), 3.52-3.69(4H, m),                                                4.13-4.22(2H, m), 4.77(1H, m),                                                5.63-5.67(1H, m), 6.81(1H, d,                                                 J=10.0Hz), 6.94-6.98(2H, m),                                                  7.04(1H, d, J=10.0Hz),                                                        7.56-7.63(2H, m).                                                                         462 (M.sup.+)                                                                     +25.9° (c                                                              = 0.94, MeOH)         70                                                                                  ##STR73##           non- crystalline solid                                                               2224, 1666, 1580 film                                                                DMSO-d.sub.6  2.72-2.88(2H, m),                                               3.21(3H, s), 3.27(3H, s),                                                     3.52-3.66(4H, m), 3.97-4.20(3H,                                               m), 4.79(1H, t, J=6.0Hz),                                                     5.67(1H, d, J=6.0Hz), 6.82(1H, d,                                             H=9.0Hz), 6.94-7.05(3H, m),                                                   7.56-7.58(2H, m).                                                                         425 (                                                                             -80.9° (c                                                              = 0.81, MeOH)         __________________________________________________________________________

                                      TABLE 36                                    __________________________________________________________________________                              m.p. (rec.                                          Ex. No.                                                                           Structural formula    from soln.)                                                                           IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                      MSm                                                                               α!.sub.D      __________________________________________________________________________    71                                                                                 ##STR74##            non- crystalline solid                                                                3316, 2927, 2224, 1737, 1663, 1574                                                  DMSO-d.sub.6  2.47-2.64(2H, m),                                               3.21(3H, s), 3.28(3H, s),                                                     3.47(3H, s), 3.53-3.66(4H, m),                                                3.98-4.14(3H, m), 4.77(1H, t,                                                 J=9.0Hz), 5.65(1H, d, J=6.0Hz),                                               6.78(1H, d, J=9.0Hz), 6.88(1H, d,                                             J=6.0Hz), 6.95(1H, d, J =6.0Hz),                                              7.00(1H, d, J=9.0Hz), 7.52(1H, br                                             s), 7.57(1H, m).                                                                            458 (M.sup.+)                                                                    -105.8°                                                                (c = 0.98,                                                                    MeOH)                72                                                                                 ##STR75##            117.5˜119.5° C. (Et.sub.2 O)                                             3301, 1658, 1580, 1511, 1488 film                                                   DMSO-d.sub.6  2.82-2.85(2H, m),                                               3.23(3H, s), 3.27(3H, s),                                                     3.51-3.65(4H, m), 3.97-4.16(3H,                                               m), 4.73(1H, t, J=7.8Hz),                                                     5.44(1H, d, J=5.5Hz), 6.78-6.83(2H                                            , m), 6.94-6.98(3H, m), 7.04(1H,                                              d, J=9.8Hz ). 418 (M.sup.+)           __________________________________________________________________________

                                      TABLE 37                                    __________________________________________________________________________                              m.p. (rec.                                          Ex. No.                                                                            Structural formula   from soln.)                                                                            IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                       MSm                                                                               α!.sub.D    __________________________________________________________________________    73                                                                                  ##STR76##           155.0˜156.0° C. (Et.sub.2 O                                               3300, 2927, 1738, 1664, 1577 film                                                   DMSO-d.sub.6  2.62-2.67(2H, m),                                               3.24(3H, s), 3.29(3H, s),                                                     3.51(3H, s), 3.52-3.66(4H, m),                                                3.97-4.14(3H, m(, 4.72(1H, t,                                                 J=8.1Hz), 5.44(1H, d, J=5.5Hz),                                               6.76-6.84(3H, m), 6.89-7.01(3H,                                               m ).           451 (M.sup.+)         74                                                                                  ##STR77##           non- crystalline solid                                                                 2224, 1672, 1574 film                                                               DMSO-d.sub.6  2.92(2H, t,                                                     J=6.0Hz), 3.23(3H, s), 3.26(3H,                                               s), 3.51-3.68(4H,                                                             m), 3.94-4.18(4H, m), 5.33(1H,                                                br s), 5.63(1H, br s), 6.38(1H,                                               d, J=9.0Hz), 6.96(1H, d,                                                      J=9.0Hz), 7.00(1H, d, J=3.0Hz),                                               7.25(1H, dd, J=9.0Hz, 3.0Hz ),                                                7.57-7.64(2H, m).                                                                            424 (M.sup.+)         __________________________________________________________________________

                                      TABLE 38                                    __________________________________________________________________________                              m.p. (rec.                                          Ex. No.                                                                           Structural formula    from soln.)                                                                          IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                       MSm                                                                               α!.sub.D      __________________________________________________________________________    75                                                                                 ##STR78##            non- crystalline solid                                                               2224, 1738, 1667, 1574 film                                                         DMSO-d.sub.6  2.70(2H, t,                                                     J=6.0Hz), 3.23(3H, s), 3.25(3H,                                               s), 3.51-3.69(7H,                                                             m), 3.94-4.05(3H, m), 4.16(1H, br                                             s), 5.28(1H, br s), 5.63(1H, br                                               s), 6.33(1H, d, J=9.0Hz), 6.93-6.97                                           (2H, m), 7.21(1H, dd, J=9.0Hz,                                                3.0Hz ), 7.58-7.65(2H,                                                                       457 (M.sup.+)           76                                                                                 ##STR79##            non- crystalline solid                                                               3375, 2927, 2224, 1664, 1578, 1560                                                  DMSO-d.sub.6  3.22(3H, s),                                                    3.28(3H, s), 3.60(4H, q, J=9.0Hz),                                            .07(1H, dd, J=9.0Hz, 6.0Hz),                                                  4.37-4.47(2H, m), 4.70-4.84(3H,                                               m), 5.62(1H, d, J=9.0Hz), 6.81(1H,                                            d, J=9.0Hz), 6.95(2H, d, J=9.0Hz),                                            .02(1H, d, J =9.0Hz), 7.47(1H, br                                             s), 7.57(1H, m).                                                                             445 (M.sup.+)                                                                    -115.3°                                                                (c = 1.08,           __________________________________________________________________________                                                             MeOH)            

                                      TABLE 39                                    __________________________________________________________________________                               m.p. (rec.                                         Ex. No.                                                                            Structural formula    from soln.)                                                                          IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                    MSm  α!.sub.D       __________________________________________________________________________    77                                                                                  ##STR80##            non- crystalline solid                                                               2224, 1665, 1577 film                                                               CDCl.sub.3  1.06(6H, t, J=6.0Hz),                                             .60(4H, q, J=6.0Hz), 3.37(3H, s),                                             3.43(3H, s), 3.68-3.82(4H, m),                                                4.22(1H, d, J=9.0Hz), 4.59-4.94(3H                                            , m), 5.10(1H, t, J=6.0Hz),                                                   6.83-6.98(3H, m), 7.44-7.47(1H,                                               m), 7.66(1H, br                                                                           495 -113.11°                                                               (c = 0.768,                                                                   MeOH)                 78                                                                                  ##STR81##            138˜142° C. (-)                                                         3354, 2930, 2226, 1728, 1666, 1574,                                           1556 film                                                                           DMSO-d.sub.6  3.21(3H, s),                                                    3.27(3H, s), 3.51-3.65(4H, m),                                                4.04-4.10(1H, m), 4.38-4.60(2H,                                               m), 4.78(1H, t, J=9.0Hz),                                                     5.67(1H, d, J=6.0Hz), 6.83(1H, d,                                             J=9.0Hz), 6.88(1H, d, J=6.0Hz),                                               6.96(1H, d, J =9.0Hz), 7.06(1H,                                               d, J=9.0Hz), 7.56-7.58(2H,                                                                430 (M.sup.+)                                                                     -115° (c =                                                             0.44, MeOH)           __________________________________________________________________________

                                      TABLE 40                                    __________________________________________________________________________                            m.p. (rec.                                            Ex. No.                                                                            Structural formula from soln.)                                                                          IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                       MSm   α!.sub.D      __________________________________________________________________________    79                                                                                  ##STR82##         non- crystalline solid                                                               2224 KBr                                                                            CDCl.sub.3  3.35(3H, s), 3.41(3H,                                             s), 3.46(1H, s), 3.60-3.90(4H, m),                                            3.90-4.30(1H, br s), 4.12(1H, dd,                                             J=3.0Hz, 9.0Hz), 4.57(1H, d,                                                  J=9.0Hz), 6.60-6.70(2H,                                                       m), 6.85-7.00(3H, m), 7.42(1H, d,                                             J=8.4Hz), 7.64(1H,                                                                           372 (                                                                              -49.8° (c                                                              = 0.78, MeOH)        80                                                                                  ##STR83##         non- crystalline solid                                                               2224 KBr                                                                            CDCl.sub.3  2.23(3H, s), 3.33(1H, d,                                          J=4.5Hz), 3.37(3H, s), 3.43(3H, s),                                           3.60-3.85(5H, m), 4.10(1H, dd,                                                J=4.5Hz, 9.2Hz), 4.57(1H, d,                                                  J=9.2Hz), 6.40-6.60(1H,                                                       m), 6.80-6.90(1H, m), 6.96(1H, d,                                             J=8.5Hz), 7.45(1H, d, J=8.5Hz),                                               7.66(1H, s) .  386 (M.sup.+)                                                                      -51.1° (c                                                              = 0.99, MeOH)        __________________________________________________________________________

                                      TABLE 41                                    __________________________________________________________________________                            m.p. (rec.                                            Ex. No.                                                                            Structural formula from soln.)                                                                          IR cm.sup.-1                                                                        .sup.1 H NMR (δ)                                                                       MSm   α!.sub.D      __________________________________________________________________________    81                                                                                  ##STR84##         non- crystalline solid                                                               2223 KBr                                                                            CDCl.sub.3  3.32(3H, s), 3.36(3H,                                             s), 3.63(1H, d, J=4.0Hz), 3.65(1H,                                            d, J=4.0Hz), 3.71(1H, d, J=7.9Hz),                                            3.92(1H, d, J=7.9Hz), 4.22(1H, d,                                             J=6.9Hz), 4.95-5.05(1H, m),                                                   6.50-6.60 (1H, m), 6.86(1H, d,                                                J=6.3Hz), 6.97(1H, d, J=6.3Hz),                                               7.15-7.45(3H , m), 7.55(1H, s),                                               7.99(1H, d, J=4.6Hz).                                                                        371 (M.sup.+)                                                                      +71.1° (c                                                              = 0.81, MeOH)        82                                                                                  ##STR85##         non- crystalline solid                                                               2223 KBr                                                                            DMSO-d.sub.6  3.23(3H, s), 3.26(3H,                                           s), 3.50-3.65(3H, m), 3.73(1H, d,                                             J=10.6Hz), 3.95-4.02(1H, m),                                                  4.50-4.60(1H, m), 5.86(1H, d,                                                 J=5.5Hz), 6.61(1H, d, J=8.5Hz),                                               6.71(1H, d, J=8.5Hz), 6.98(1H, d,                                             J=8.8Hz), 7.05-7.15(1H, m), 7.49(1H,                                          d, J=6.0Hz) , 7.55-7.70(2H, m),                                               7.76(1H, s).   371 (M.sup.+)                                                                      +21.1° (c                                                              = 0.61, MeOH)        __________________________________________________________________________

                                      TABLE 42                                    __________________________________________________________________________                            m.p. (rec.                                            Ex. No.                                                                            Structural formula from soln.)                                                                            IR cm.sup.-1                                                                         .sup.1 H NMR (δ)                                                                    MSm   α!.sub.D      __________________________________________________________________________    83                                                                                  ##STR86##         147.0˜149.2° C. (AcOEt- n-Hexane)                                         2226, 1655, 1624, 1600, 1490 KBr                                                     CDCl.sub.3  3.40(3H, s), 3.48(3H,                                             s), 3.40-3.60(1H,                                                             m), 3.70-3.95(4H,                                                             m), 4.30-4.42(1H, m), 6.58(1H, d,                                             J=6.0Hz), 6.65-6.80(2H, m),                                                   7.04(1H, d, J=6.0Hz), 7.40-7.75(4H                                            , m), 8.49(1H, d, J                                                                       406 (M.sup.+)                                                                      -74.7° (c                                                              = 0.95, CHCl.sub.                                                             3)                   84                                                                                  ##STR87##         133.9˜135.0° C. (EtOH)                                                    2224, 1631, 1591, 1577 KBr                                                           CDCl.sub.3  3.30(3H, s), 3.47(3H,                                             s), 3.75(1H, d, J=9.0Hz),                                                     3.78(2H, s), 3.96(1H, d,                                                      J=9.0Hz), 4.45(1H, d, J=9.0Hz),                                               6.06(1H, d, J=9.0Hz), 6.33(1H,                                                s), 7.02(1H, d, J=9.0Hz),                                                     7.34(1H, s), 7.40-8.00(6H, m),                                                8.95(1H, s ).                                                                             406 (M.sup.+)                                                                      +23.9° (c                                                              = 1.04, CHCl.sub.                                                             3)                   __________________________________________________________________________

                                      TABLE 43                                    __________________________________________________________________________                             m.p. (rec.                                           Ex. No.                                                                            Structural formula  from soln.)                                                                          IR cm.sup.-1                                                                          .sup.1 H NMR (δ)                                                                    MSm   α!.sub.D      __________________________________________________________________________    85                                                                                  ##STR88##          non- crystalline solid                                                               2225, 1641, 1585, 1490 KBr                                                            CDCl.sub.3  3.37(3H, s), 3.41(3H,                                             s) 3.70-4.00(4H, m), 3.78(3H, s),                                             4.42(1H, s), 4.50-4.60(1H, m),                                                6.21(1H, d, J=6.0Hz), 7.04(1H, d,                                             J=9.0Hz), 7.53(1H, d, J=9.0Hz),                                               7.66(1H, s), 7.75-7.85(2H, m),                                                7.90-7.95(1H, m ). 8.40-8.45(1H,                                              m).         437 (M.sup.+)                                                                      -57.2° (c                                                              = 1.01, MeOH)        86                                                                                  ##STR89##          non- crystalline solid                                                               2225, 1647, 1588 KBr                                                                  CDCl.sub.3  2.12(3H, s), 2.20(3H,                                             s), 3.39(3H, s), 3.41(3H, s),                                                 3.65-3.95(7H, m), 4.22-4.24(1H,                                               m), 4.40-4.44(1H, m), 6.02(1H, d,                                             J=9.0Hz), 7.01(1H, d, J=9.0Hz),                                               7.50(1H, d, J=9.0Hz), 7.59(1H,                                                s).         415                                                                                -104.6°                                                                (c = 0.98,           __________________________________________________________________________                                                             MeOH)            

                                      TABLE 44                                    __________________________________________________________________________                             m.p. (rec.                                           Ex. No.                                                                            Structural formula  from soln.)                                                                          IR cm.sup.-1                                                                          .sup.1 H NMR (δ)                                                                    MSm   α!.sub.D      __________________________________________________________________________    87                                                                                  ##STR90##          non- crystalline solid                                                               1654, 1578 KBr                                                                        CDCl.sub.3  3.35(3H, s), 3.42(3H,                                             s), 3.60-4.00(5H, m), 3.77(3H,                                                s), 4.35-4.45(1H, m), 5.89(1H, d,                                             J=6.0Hz), 6.83(1H, d, J=9.0Hz),                                               6.97(2H, s), 7.30-7.35(2H,                                                                440 (M.sup.+) 442                                                             (M.sup.+)                                                                          -71.2 °                                                                (c = 0.59,                                                                    MeOH)                88                                                                                  ##STR91##          non- crystalline solid                                                               1662, 1585, 1436 KBr                                                                  CDCl.sub.3  3.37(3H, s), 3.41(3H,                                             s), 3.6-4.1(5H, m), 3.72(3H, s),                                              4.45-4.55(1H, m), 5.99(1H, d,                                                 J=6.0Hz), 7.00(2H, s), 7.03(1H,                                               d, J=9.0Hz), 8.14(1H, d,                                                      J=9.0Hz), 8.25(1H,                                                                        407 (M.sup.+)                                                                      -102.3 °                                                               (c = 1.0,                                                                     CHCl.sub.3)          __________________________________________________________________________

FORMULATION EXAMPLE 1: TABLET

    ______________________________________                                        Compound of Example 28                                                                           1      g                                                   Lactose            3      kg                                                  Hydroxypropyl cellulose                                                                          200    g                                                   Starch             1      kg                                                  Talc               10     g                                                   Magnesium stearate 10     g                                                   ______________________________________                                    

The above ingredients were compressed by a conventional method to givetablets containing 0.1 mg of an active substance per tablet.

FORMULATION EXAMPLE 2: CAPSULE

    ______________________________________                                        Compound of Example 28                                                                           1      g                                                   Lactose            2      kg                                                  Magnesium stearate 10     g                                                   ______________________________________                                    

The above ingredients were filled in hard gelatin capsules by aconventional method to give capsules containing 0.1 mg of an activesubstance per capsule.

What is claimed is:
 1. A chroman compound of the formula I! ##STR92##wherein R¹ is a cyano, a nitro, a trihalomethyl, a trihalomethoxy or ahalogen atom;R² is a lower alkoxyalkyl wherein the total carbon numberof the alkoxy moiety and alkyl moiety is 2 to 6, a phenyloxy C₁ -C₅alkyl or a dialkoxyalkyl having 3 to 8 carbon atoms; R³ is a loweralkoxyalkyl wherein the total carbon number of the alkoxy moiety andalkyl moiety is 2 to 6 or a phenyloxy C₁ -C₅ alkyl; R⁴ is a hydroxy, aformyloxy or a lower alkanoyloxy; X is N--H, an oxygen atom or a sulfuratom; and Y is a dihydrooxopyridazinyl or dihydrothioxopyridazinyloptionally substituted by 1 to 3 substituents selected from the groupconsisting oflower alkyl having 1 to 7 carbon atoms optionallymonosubstituted by a substituent selected from the group consisting ofnitro, halogen atom, cyano, lower alkoxy having 1 to 4 carbon atoms,cycloalkyl having 3 to 6 carbon atoms, lower alkylsulfonyl having 1 to 4carbon atoms, lower alkylsulfinyl having 1 to 4 carbon atoms, carboxyl,di-lower alkylamino having 1 to 6 carbon atoms, alkylthio having 1 to 4carbon atoms, benzyloxycarbonyl and lower alkoxycarboxyl having 2 to 5carbon atoms: lower alkenyl having 2 to 4 carbon atoms: phenyloptionally mono-substituted by nitro and benzyl, or a pharmaceuticallyacceptable salt thereof.
 2. The chroman compound of claim 1, wherein R¹is a cyano, a nitro or a halogen atom, R² is a lower alkoxyalkyl whereinthe total carbon number of the alkoxy moiety and alkyl moiety is 2 to 6,R³ is a lower alkoxyalkyl wherein the total carbon number of the alkoxymoiety and alkyl moiety is 2 to 6, R⁴ is a hydroxy and X is N--H or anoxygen atom, or a pharmaceutically acceptable salt thereof.
 3. Thechroman compound of claim 2, wherein X is N--H, R¹ is a cyano, R² is amethoxymethyl and R³ is a methoxymethyl, or a pharmaceuticallyacceptable salt thereof.
 4. The chroman compound of claim 3, wherein Xis N--H and Y is 1,6-dihydro-1-C₁ -C₅ alkyl-6-oxo-3-pyridazinyl or1,6-dihydro-1-substituted C₁ -C₅ alkyl-6-oxo-3-pyridazinyl, or apharmaceutically acceptable salt thereof.
 5. The chroman compound ofclaim 1, which is a member selected from the group consistingof(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,(-)-(3S,4R)-6-cyano-4-(1-ethyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-isopropyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,(-)-(3S,4R)-6-cyano-3,4-dihydro-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino!-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-olhydrate and (-)-(3S,4R)-6-cyano-4-(1-cyclopropylmethyl-1,6-dihydro-6-oxo-3-pyridazinyl)amino!-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol,or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising the chroman compound of claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 7. A pharmaceutical composition comprising thechroman compound of claim 5 or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.
 8. A method ofpreventing or treating cardiovascular disorders which comprisesadministering to a patient in need of treatment an effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof.
 9. Amethod of preventing or treating cardiovascular disorders whichcomprises administering to a patient in need of treatment an effectiveamount of a compound of claim 5, or a pharmaceutically acceptable saltthereof.